Acetyl CoA carboxylase modulators

ABSTRACT

Provided herein are compounds that exhibit activity as acetyl-CoA carboxylase modulators (e.g., inhibitors) and are useful, for example, in methods for the control of fungal pathogens in plants.

REFERENCE TO RELATED APPLICATIONS

The present application is the 371 National Stage Application ofInternational PCT Application No. PCT/US2014/042267, filed Jun. 13,2014, which claims the benefit of U.S. Provisional Application No.61/834,585, filed Jun. 13, 2013, the entire contents of which areincorporated herein by reference.

FIELD

Provided herein are compounds that exhibit activity as acetyl-CoAcarboxylase modulators (e.g., inhibitors) and are useful, for example,in methods for the control of fungal pathogens and diseases caused byfungal pathogens in plants.

BACKGROUND

Acetyl-CoA carboxylase (“ACCase”) is an essential catalyst for therate-limiting step of fatty acid biosynthesis in both eukaryotes andprokaryotes. Phytopathogenic fungi can infect crop plants either in thefield or after harvesting, resulting in considerable economic losses tofarmers and producers worldwide. In addition to the agricultural impact,when food and feed contaminated with fungi or the toxins they produceare ingested by humans or livestock, a number of debilitating diseasesor death can occur. Approximately 10,000 species of fungi are known todamage crops and affect quality and yield. Crop rotation, breeding ofresistantcultivars, the application of agrochemicals and combinations ofthese strategies is commonly employed to stem the spread of fungalpathogens and the diseases they cause. Additional chemistry and methodsof using such as a modulator for ACCase or to control fungi areimportant for, among other things, protection in agriculture.

For example, the rapid onset of resistance to chemical fungicides hasoften lowered the efficacy of some chemical fungicides. This threat, aswell as emergence and spread of additional fungal diseases, accentuatesthe need for new means of fungal control.

SUMMARY

In one aspect, therefore, the present disclosure is directed to acompound of Formula I or a salt thereof,

wherein R¹ is selected from the group consisting of hydrogen, halogen,alkyl, alkoxy, haloalkyl, and haloalkoxy; R² is selected from the groupconsisting of aryl and heteroaryl, each of which may be optionallyindependently substituted with one or more substituents selected fromthe group consisting of halogen, OH, CN, alkyl, alkoxy, haloalkyl,haloalkoxy, alkenyl, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), and NR⁹C(O)R¹⁰,wherein R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen and alkyl, and wherein R⁹ is selected from thegroup consisting of hydrogen and alkyl and R¹⁰ is alkyl; R³, R⁴, R⁵, andR⁶ are each independently selected from the group consisting ofhydrogen, halogen, OH, alkyl, alkoxy, haloalkyl, haloalkoxy, C₁ to C₄hydroxyalkyl, N(R⁷R⁸), NR⁹C(O)R¹⁰, and C(O)R¹¹, wherein R⁷ and R⁸ areeach independently selected from the group consisting of hydrogen andalkyl, and wherein R⁹ is selected from the group consisting of hydrogenand alkyl and R¹⁰ and R¹¹ are alkyl; X is selected from the groupconsisting of a bond, CH₂, O, S, NH, and N(CH₃); Y is selected from thegroup consisting of OH, NH₂, N(H)OH, N(CH₃)OH, and N(R⁷R⁸), wherein R⁷and R⁸ are each independently selected from the group consisting ofhydrogen, alkyl, and hydroxyalkyl; and Z is selected from the groupconsisting of aryl and heteroaryl, each of which may be optionallyindependently substituted with one or more substituents selected fromthe group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy,C₁ to C₄ hydroxyalkyl, CN, and C(H)O.

In another aspect, the present disclosure is directed to a compound ofFormula II or a salt thereof,

wherein R¹ is selected from the group consisting of hydrogen, halogen,alkyl, alkoxy, haloalkyl, and haloalkoxy; R² is selected from the groupconsisting of aryl and heteroaryl, each of which may be optionallyindependently substituted with one or more substituents selected fromthe group consisting of halogen, OH, CN, alkyl, alkoxy, haloalkyl,haloalkoxy, alkenyl, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), and NR⁹C(O)R¹⁰,wherein R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen and alkyl, and wherein R⁹ is selected from thegroup consisting of hydrogen and alkyl and R¹⁰ is alkyl; R³, R⁴, R⁵, andR⁶ are each independently selected from the group consisting ofhydrogen, halogen, OH, alkyl, alkoxy, haloalkyl, haloalkoxy, C₁ to C₄hydroxyalkyl, N(R⁷R⁸), NR⁹C(O)R¹⁰, and C(O)R¹¹, wherein R⁷ and R⁸ areeach independently selected from the group consisting of hydrogen andalkyl, and wherein R⁹ is selected from the group consisting of hydrogenand alkyl and R¹⁰ and R¹¹ are alkyl; X is selected from the groupconsisting of a bond, CH₂, O, S, NH, and N(CH₃); Y is selected from thegroup consisting of hydrogen, a prodrug of a carboxylic acid and acarboxylic acid isostere; and Z is selected from the group consisting ofaryl and heteroaryl, each of which may be optionally independentlysubstituted with one or more substituents selected from the groupconsisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, C₁ to C₄hydroxyalkyl, CN, and C(H)O. In some embodiments, when R² is phenyl, Zis phenyl, and Y is C(O)OCH₂CH₃, R⁴ is other than halogen.

In another aspect, the present disclosure is directed to a compound ofFormula III or a salt thereof,

wherein R¹ is selected from the group consisting of hydrogen, halogen,alkyl, alkoxy, haloalkyl, and haloalkoxy; R² is selected from the groupconsisting of aryl and heteroaryl, each of which may be optionallyindependently substituted with one or more substituents selected fromthe group consisting of halogen, OH, CN, alkyl, alkoxy, haloalkyl,haloalkoxy, alkenyl, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), and NR⁹C(O)R¹⁰,wherein R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen and alkyl, and wherein R⁹ is selected from thegroup consisting of hydrogen and alkyl and R¹⁰ is alkyl; R³, R⁴, R⁵, andR⁶ are each independently selected from the group consisting ofhydrogen, halogen, OH, alkyl, alkoxy, haloalkyl, haloalkoxy, C₁ to C₄hydroxyalkyl, N(R⁷R⁸), NR⁹C(O)R¹⁰, and C(O)R¹¹, wherein R⁷ and R⁸ areeach independently selected from the group consisting of hydrogen andalkyl, and wherein R⁹ is selected from the group consisting of hydrogenand alkyl and R¹⁰ and R¹¹ are alkyl; X is selected from the groupconsisting of CH₂, O, S, NH, and N(CH₃); Y is selected from the groupconsisting of OH, NH₂, N(H)OH, N(CH₃)OH, and N(R⁷R⁸), wherein R⁷ and R⁸are each independently selected from the group consisting of hydrogen,alkyl, and hydroxyalkyl; and Z is selected from the group consisting ofhydrogen, alkyl, haloalkyl, and cycloalkyl.

In another aspect, the present disclosure is directed to a compound ofFormula IV or a salt thereof,

wherein R¹ is selected from the group consisting of hydrogen, halogen,alkyl, alkoxy, haloalkyl, and haloalkoxy; R² is selected from the groupconsisting of aryl and heteroaryl, each of which may be optionallyindependently substituted with one or more substituents selected fromthe group consisting of halogen, OH, CN, alkyl, alkoxy, haloalkyl,haloalkoxy, alkenyl, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), and NR⁹C(O)R¹⁰,wherein R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen and alkyl, and wherein R⁹ is selected from thegroup consisting of hydrogen and alkyl and R¹⁰ is alkyl; R³, R⁴, R⁵, andR⁶ are each independently selected from the group consisting ofhydrogen, halogen, OH, alkyl, alkoxy, haloalkyl, haloalkoxy, C₁ to C₄hydroxyalkyl, N(R⁷R⁸), NR⁹C(O)R¹⁰, and C(O)R¹¹, wherein R⁷ and R⁸ areeach independently selected from the group consisting of hydrogen andalkyl, and wherein R⁹ is selected from the group consisting of hydrogenand alkyl and R¹⁰ and R¹¹ are alkyl; and Z is selected from the groupconsisting of aryl and heteroaryl, each of which may be optionallyindependently substituted with one or more substituents selected fromthe group consisting of halogen, alkyl, alkoxy, haloalkyl, andhaloalkoxy, C₁ to C₄ hydroxyalkyl, CN, and C(H)O.

Another aspect of the present disclosure is directed to a compoundselected from the group consisting of:2-(4-(4-phenylquinolin-2-yl)phenoxy)acetamide, or a salt thereof,2-(4-(4-phenylquinolin-2-yl)phenoxy)acetic acid, or a salt thereof,2-(4-(8-methoxy-4-phenylquinolin-2-yl)phenoxy)acetamide, or a saltthereof, 2-(4-(8-ethyl-4-phenylquinolin-2-yl)phenoxy)acetamide, or asalt thereof,2-(4-(6-chloro-4-phenylquinolin-2-yl)phenoxy)-N-(2-hydroxyethyl)acetamide,or a salt thereof,2-(5-(3-chloro-4-phenylquinolin-2-yl)thiophen-2-yl)acetamide, or a saltthereof, 2-(5-(3-chloro-4-phenylquinolin-2-yl)thiophen-2-yl)acetic acid,or a salt thereof, 2-(5-(4-phenylquinolin-2-yl)thiophen-2-yl)acetamide,or a salt thereof, 2-(5-(4-phenylquinolin-2-yl)thiophen-2-yl)aceticacid, or a salt thereof,2-(5-(8-methoxy-4-phenylquinolin-2-yl)thiophen-2-yl)acetamide, or a saltthereof, 2-(5-(8-ethyl-4-phenylquinolin-2-yl)thiophen-2-yl)acetamide, ora salt thereof,2-(4-((1H-tetrazol-5-yl)methoxy)phenyl)-4-phenylquinoline, or a saltthereof, ((4-(4-phenylquinolin-2-yl)phenoxy)methyl)phosphonic acid, or asalt thereof, ((4-(4-phenylquinolin-2-yl)phenoxy)methyl)phosphinic acid,or a salt thereof, (4-(4-phenylquinolin-2-yl)phenoxy)methanesulfonicacid, or a salt thereof,(4-(4-phenylquinolin-2-yl)phenoxy)methanesulfonamide, or a salt thereof,N-(methyl sulfonyl)-2-(4-(4-phenylquinolin-2-yl)phenoxy)acetamide, or asalt thereof,5-((4-(4-phenylquinolin-2-yl)phenoxy)methyl)thiazolidine-2,4-dione, or asalt thereof,5-((4-(4-phenylquinolin-2-yl)phenoxy)methyl)oxazolidine-2,4-dione, or asalt thereof,3-((4-(4-phenylquinolin-2-yl)phenoxy)methyl)-1,2,4-oxadiazol-5(4H)-one,or a salt thereof,2-(5-((1H-tetrazol-5-yl)methyl)thiophen-2-yl)-4-phenylquinoline, or asalt thereof,(((5-(4-phenylquinolin-2-yl)thiophen-2-yl)methyl)phosphonic acid, or asalt thereof,(((5-(4-phenylquinolin-2-yl)thiophen-2-yl)methyl)phosphinic acid, or asalt thereof, ((5-(4-phenylquinolin-2-yl)thiophen-2-yl)methanesulfonicacid, or a salt thereof,((5-(4-phenylquinolin-2-yl)thiophen-2-yl)methanesulfonamide, or a saltthereof,N-(methylsulfonyl)-2-(5-(4-phenylquinolin-2-yl)thiophen-2-yl)acetamide,or a salt thereof,5-(((5-(4-phenylquinolin-2-yl)thiophen-2-yl)methyl)thiazolidine-2,4-dione,or a salt thereof,5-(((5-(4-phenylquinolin-2-yl)thiophen-2-yl)methyl)oxazolidine-2,4-dione,or a salt thereof,3-(((5-(4-phenylquinolin-2-yl)thiophen-2-yl)methyl)-1,2,4-oxadiazol-5(4H)-one,or a salt thereof, methyl 2-(4-(4-phenylquinolin-2-yl)phenoxy)acetate,or a salt thereof, methyl2-(5-(4-phenylquinolin-2-yl)thiophen-2-yl)acetate, or a salt thereof,methyl 2-(5-(3-chloro-4-phenylquinolin-2-yl)thiophen-2-yl)acetate, or asalt thereof, 2-((7-methoxy-4-phenylquinolin-2-yl)thio)propanamide, or asalt thereof, 2-(4-methoxyphenyl)-4-phenylquinoline, or a salt thereof,and 2-(3,4-dimethoxyphenyl)-4-phenylquinoline, or a salt thereof.

Another aspect of the present disclosure is generally related to amethod of controlling fungal pathogens comprising administering to aplant, a seed or soil a composition comprising an effective amount of acompound as described herein.

Another aspect of the present disclosure is generally related to amethod for modulating ACCase in a biological organism comprisingadministering to the biological organism a composition comprising aneffective amount of a compound as described herein.

Another aspect of the present disclosure is generally related to acomposition comprising a compound as described herein.

Another aspect of the present disclosure is generally related to a seedcomprising a coating comprising a compound or a composition as describedherein.

Other objects and features will be in part apparent and in part pointedout hereinafter.

DETAILED DESCRIPTION

Described herein are compounds that exhibit activity as acetyl-CoAcarboxylase (ACCase) modulators. The compounds described herein may beused, for example, in the preparation of compositions and in accordancewith methods for control of fungal pathogens, as set forth in detailbelow.

For example, in one embodiment, the compound is a compound of Formula Ior a salt thereof,

wherein

R¹ is selected from the group consisting of hydrogen, halogen, alkyl,alkoxy, haloalkyl, and haloalkoxy;

R² is selected from the group consisting of aryl and heteroaryl, each ofwhich may be optionally independently substituted with one or moresubstituents selected from the group consisting of halogen, OH, CN,alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, C₁ to C₄ hydroxyalkyl,N(R⁷R⁸), and NR⁹C(O)R¹⁰, wherein R⁷ and R⁸ are each independentlyselected from the group consisting of hydrogen and alkyl, and wherein R⁹is selected from the group consisting of hydrogen and alkyl and R¹⁰ isalkyl;

R³, R⁴, R⁵, and R⁶ are each independently selected from the groupconsisting of hydrogen, halogen, OH, alkyl, alkoxy, haloalkyl,haloalkoxy, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), NR⁹C(O)R¹⁰, and C(O)R¹¹,wherein R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen and alkyl and wherein R⁹ is selected from thegroup consisting of hydrogen and alkyl and R¹⁰ and R¹¹ are alkyl;

X is selected from the group consisting of a bond, CH₂, O, S, NH, andN(CH₃);

Y is selected from the group consisting of OH, NH₂, N(H)OH, N(CH₃)OH,and N(R⁷R⁸) wherein R⁷ and R⁸ are each independently selected from thegroup consisting of hydrogen, alkyl, and hydroxyalkyl; and

Z is selected from the group consisting of aryl and heteroaryl, each ofwhich may be optionally independently substituted with one or moresubstituents selected from the group consisting of halogen, alkyl,alkoxy, haloalkyl, haloalkoxy, C₁ to C₄ hydroxyalkyl, CN, and C(H)O.

In some embodiments, R² is selected from the group consisting of aryland heteroaryl, each of which may be optionally independentlysubstituted with one or more substituents selected from the groupconsisting of halogen, OH, CH₃, OCH₃, CF₃, OCF₃, and CN. For example, insome embodiments, R² is phenyl.

In some embodiments, Z is selected from the group consisting of aryl andheteroaryl, each of which may be optionally independently substitutedwith one or more substituents selected from the group consisting ofhalogen, CH₃, OCH₃, CF₃, OCF₃, CN, and C(H)O.

For example, in some embodiments, Z is selected from the groupconsisting of phenyl and thienyl. In some embodiments, Z is phenyl. Inother embodiments, Z is thienyl.

For example, the compound of Formula I may be a compound of Formula Iaor a salt thereof,

wherein

R¹ is selected from the group consisting of hydrogen, halogen, alkyl,alkoxy, haloalkyl, and haloalkoxy;

R³, R⁴, R⁵, and R⁶ are each independently selected from the groupconsisting of hydrogen, halogen, OH, alkyl, alkoxy, haloalkyl,haloalkoxy, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), NR⁹C(O)R¹⁰, and C(O)R¹¹,wherein R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen and alkyl, and wherein R⁹ is selected from thegroup consisting of hydrogen and alkyl and R¹⁰ and R¹¹ are alkyl;

X is selected from the group consisting of CH₂, O, S, NH, and N(CH₃);and

Y is selected from the group consisting of OH, NH₂, N(H)OH, N(CH₃)OH,and N(R⁷R⁸), wherein R⁷ and R⁸ are each independently selected from thegroup consisting of hydrogen, alkyl, and hydroxyalkyl.

Alternatively, the compound of Formula I may be a compound of Formula Ibor a salt thereof,

wherein

R¹ is selected from the group consisting of hydrogen, halogen, alkyl,alkoxy, haloalkyl, and haloalkoxy;

R³, R⁴, R⁵, and R⁶ are each independently selected from the groupconsisting of hydrogen, halogen, OH, alkyl, alkoxy, haloalkyl,haloalkoxy, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), and NR⁹C(O)R¹⁰, wherein R⁷and R⁸ are each independently selected from the group consisting ofhydrogen and alkyl, and wherein R⁹ is selected from the group consistingof hydrogen and alkyl and R¹⁰ and R¹¹ are alkyl;

Y is selected from the group consisting of OH, NH₂, N(H)OH, N(CH₃)OH,and N(R⁷R⁸), wherein R⁷ and R⁸ are each independently selected from thegroup consisting of hydrogen, alkyl, and hydroxyalkyl; and

E is selected from the group consisting of S, O, and N(CH₃).

In some embodiments, the compound is a compound of formula Ib wherein Eis S. In other embodiments, E is O. In still further embodiments, E isN(CH₃).

In some embodiments, the compound is a compound of Formula I, Ia, or Ibwherein R¹ is selected from the group consisting of hydrogen, halogen,CH₃, OCH₃, CF₃, and OCF₃. In some embodiments, R¹ is hydrogen. In otherembodiments, R¹ is halogen.

In some embodiments, the compound is a compound of Formula I, Ia, or Ibwherein R³, R⁴, R⁵, and R⁶ are each independently selected from thegroup consisting of hydrogen, halogen, OH, CH₃, OCH₃, CF₃, and OCF₃. Forexample, in some embodiments, R³, R⁴, R⁵, and R⁶ are each hydrogen.

In some embodiments, the compound is a compound of Formula I or Iawherein X is selected from the group consisting of a bond and S. Forexample, in some embodiments, X is a bond. In other embodiments, X is S.

In some embodiments, the compound is a compound of Formula I, Ia, or Ibwherein Y is selected from the group consisting of OH and NH₂. In someembodiments, Y is OH. In other embodiments, Y is NH₂.

In another embodiment, the compound is a compound of Formula II or asalt thereof,

wherein

R¹ is selected from the group consisting of hydrogen, halogen, alkyl,alkoxy, haloalkyl, and haloalkoxy;

R² is selected from the group consisting of aryl and heteroaryl, each ofwhich may be optionally independently substituted with one or moresubstituents selected from the group consisting of halogen, OH, CN,alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, C₁ to C₄ hydroxyalkyl,N(R⁷R⁸), and NR⁹C(O)R¹⁰, wherein R⁷ and R⁸ are each independentlyselected from the group consisting of hydrogen and alkyl, and wherein R⁹is selected from the group consisting of hydrogen and alkyl and R¹⁰ isalkyl;

R³, R⁴, R⁵, and R⁶ are each independently selected from the groupconsisting of hydrogen, halogen, OH, alkyl, alkoxy, haloalkyl,haloalkoxy, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), NR⁹C(O)R¹⁰, and C(O)R¹¹,wherein R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen and alkyl, and wherein R⁹ is selected from thegroup consisting of hydrogen and alkyl and R¹⁰ and R¹¹ are alkyl;

X is selected from the group consisting of a bond, CH₂, O, S, NH, andN(CH₃);

Y is selected from the group consisting of hydrogen, a prodrug of acarboxylic acid and a carboxylic acid isostere; and

Z is selected from the group consisting of aryl and heteroaryl, each ofwhich may be optionally independently substituted with one or moresubstituents selected from the group consisting of halogen, alkyl,alkoxy, haloalkyl, and haloalkoxy, C₁ to C₄ hydroxyalkyl, CN, and C(H)O.

In some embodiments, when R² is phenyl, Z is phenyl, and Y isC(O)OCH₂CH₃, R⁴ is other than halogen.

In some embodiments, R² is selected from the group consisting of aryland heteroaryl, each of which may be optionally independentlysubstituted with one or more substituents selected from the groupconsisting of halogen, OH, CH₃, OCH₃, CF₃, OCF₃, and CN. For example, insome embodiments, R² is phenyl.

In some embodiments, Z is selected from the group consisting of aryl andheteroaryl, each of which may be optionally independently substitutedwith one or more substituents selected from the group consisting ofhalogen, CH₃, OCH₃, CF₃, OCF₃, CN, and C(H)O.

For example, in some embodiments, Z is selected from the groupconsisting of phenyl and thienyl. In some embodiments, Z is phenyl. Inother embodiments, Z is thienyl.

For example, the compound of Formula II may be a compound of Formula IIaor a salt thereof,

wherein

R¹ is selected from the group consisting of hydrogen, halogen, alkyl,alkoxy, haloalkyl, and haloalkoxy;

R³, R⁴, R⁵, and R⁶ are each independently selected from the groupconsisting of hydrogen, halogen, OH, alkyl, alkoxy, haloalkyl,haloalkoxy, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), NR⁹C(O)R¹⁰, and C(O)R¹¹,wherein R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen and alkyl, and wherein R⁹ is selected from thegroup consisting of hydrogen and alkyl and R¹⁰ and R¹¹ are alkyl;

X is selected from the group consisting of CH₂, O, S, NH, and N(CH₃);and Y is selected from the group consisting of hydrogen and a carboxylicacid isostere.

Alternatively, the compound of Formula II may be a compound of FormulaIIb or a salt thereof,

wherein

R¹ is selected from the group consisting of hydrogen, halogen, alkyl,alkoxy, haloalkyl, and haloalkoxy;

R³, R⁴, R⁵, and R⁶ are each independently selected from the groupconsisting of hydrogen, halogen, OH, alkyl, alkoxy, haloalkyl,haloalkoxy, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸) NR⁹C(O)R¹⁰, and C(O)R¹¹,wherein R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen and alkyl, and wherein R⁹ is selected from thegroup consisting of hydrogen and alkyl and R¹⁰ and R¹¹ are alkyl;

Y is a carboxylic acid isostere; and

E is selected from the group consisting of S, O, and N(CH₃).

In another embodiment, the compound of Formula II may be a compound ofFormula IIc or a salt thereof,

wherein

R¹ is selected from the group consisting of hydrogen, halogen, alkyl,alkoxy, haloalkyl, and haloalkoxy;

R³, R⁴, R⁵, and R⁶ are each independently selected from the groupconsisting of hydrogen, halogen, OH, alkyl, alkoxy, haloalkyl,haloalkoxy, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), NR⁹C(O)R¹⁰, and C(O)R¹¹,wherein R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen and alkyl, and wherein R⁹ is selected from thegroup consisting of hydrogen and alkyl and R¹⁰ and R¹¹ are alkyl;

X is selected from the group consisting of CH₂, O, S, NH, and N(CH₃);and

Y is selected from the group consisting of hydrogen and a prodrug ofcarboxylic acid.

In some embodiments, when Y is C(O)OCH₂CH₃, R⁴ is other than halogen.

In a further embodiment, the compound of Formula II may be a compound ofFormula IId or a salt thereof,

wherein

R¹ is selected from the group consisting of hydrogen, halogen, alkyl,alkoxy, haloalkyl, and haloalkoxy;

R³, R⁴, R⁵, and R⁶ are each independently selected from the groupconsisting of hydrogen, halogen, OH, alkyl, alkoxy, haloalkyl,haloalkoxy, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), NR⁹C(O)R¹⁰, and C(O)R¹¹,wherein R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen and alkyl, and wherein R⁹ is selected from thegroup consisting of hydrogen and alkyl and R¹⁰ and R¹¹ are alkyl;

Y is a prodrug of carboxlic acid; and

E is selected from the group consisting of S, O, and N(CH₃).

In some embodiments, the compound is a compound of formula IIb or IIdwherein E is S. In other embodiments, E is O. In still furtherembodiments, E is N(CH₃).

In some embodiments, the compound is a compound of Formula II, IIa, IIb,IIc, or IId wherein R¹ is selected from the group consisting ofhydrogen, halogen, CH₃, OCH₃, CF₃, and OCF₃. In some embodiments, R¹ ishydrogen. In other embodiments, R¹ is halogen.

In some embodiments, the compound is a compound of Formula II, IIa, IIb,IIc, or IId wherein R³, R⁴, R⁵, and R⁶ are each independently selectedfrom the group consisting of hydrogen, halogen, OH, CH₃, OCH₃, CF₃, andOCF₃. For example, in some embodiments, R³, R⁴, R⁵, and R⁶ are eachhydrogen.

In some embodiments, the compound is a compound of Formula II, IIa, orIIc wherein X is selected from the group consisting of a bond and O. Forexample, in some embodiments, X is a bond. In other embodiments, X is O.

In some embodiments, the compound is a compound of Formula II, IIa, orIIb wherein Y is a carboxylic acid isostere selected from the groupconsisting of tetrazolyl, aminosulfonyl, acylaminosulfonyl, methylsulfonylcarbamyl, thiazolidinedionyl, oxazolidinedionyl, oxadiazolonyl,P(O)(OH)₂, P(O)(OH)H, and SO₃H.

In some embodiments, the compound is a compound of Formula II, IIc, orIId wherein Y is a prodrug of carboxylic acid selected from the groupconsisting of CH₂OH and an ester group C(O)OR¹¹; wherein R¹¹ is selectedfrom the group consisting of methyl, ethyl, 2-oxopropyl,2-morpholinoethyl and pivaloyloxymethyl. For example, in someembodiments, Y is C(O)OCH₃. In other embodiments, Y is CH₂OH. In stillfurther embodiments, Y is methoxy.

In another embodiment, the compound is a compound of Formula III or asalt thereof,

wherein

R¹ is selected from the group consisting of hydrogen, halogen, alkyl,alkoxy, haloalkyl, and haloalkoxy;

R² is selected from the group consisting of aryl and heteroaryl, each ofwhich may be optionally independently substituted with one or moresubstituents selected from the group consisting of halogen, OH, CN,alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, C₁ to C₄ hydroxyalkyl,N(R⁷R⁸) and NR⁹C(O)R¹⁰, wherein R⁷ and R⁸ are each independentlyselected from the group consisting of hydrogen and alkyl, and wherein R⁹is selected from the group consisting of hydrogen and alkyl and R¹⁰ isalkyl;

R³, R⁴, R⁵, and R⁶ are each independently selected from the groupconsisting of hydrogen, halogen, OH, alkyl, alkoxy, haloalkyl,haloalkoxy, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), NR⁹C(O)R¹⁰, and C(O)R¹¹,wherein R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen and alkyl, and wherein R⁹ is selected from thegroup consisting of hydrogen and alkyl and R¹⁰ and R¹¹ are alkyl;

X is selected from the group consisting of CH₂, O, S, NH, and N(CH₃);

Y is selected from the group consisting of OH, NH₂, N(H)OH, N(CH₃)OH,and N(R⁷R⁸), wherein R⁷ and R⁸ are each independently selected from thegroup consisting of hydrogen, alkyl, and hydroxyalkyl; and

Z is selected from the group consisting of hydrogen, alkyl, haloalkyl,and cycloalkyl.

In some embodiments, R² is selected from the group consisting of aryland heteroaryl, each of which may be optionally independentlysubstituted with one or more substituents selected from the groupconsisting of halogen, OH, CH₃, OCH₃, CF₃, OCF₃, and CN. For example, insome embodiments, R² is phenyl.

In some embodiments, the compound is a compound of Formula III whereinR¹ is selected from the group consisting of hydrogen, halogen, CH₃,OCH₃, CF₃, and OCF₃. In some embodiments, R¹ is hydrogen. In otherembodiments, R¹ is halogen.

In some embodiments, the compound is a compound of Formula III whereinR³, R⁴, R⁵, and R⁶ are each independently selected from the groupconsisting of hydrogen, halogen, OH, CH₃, OCH₃, CF₃, and OCF₃. In someembodiments, R³, R⁴, R⁵, and R⁶ are each hydrogen.

In some embodiments, the compound is a compound of Formula III wherein Xis S.

In some embodiments, the compound is a compound of Formula III wherein Yis selected from the group consisting of OH and NH₂. For example, insome embodiments, Y is OH. In other embodiments, Y is NH₂.

In some embodiments, the compound is a compound of Formula III wherein Zis alkyl. For example, in some embodiments, Z is CH₃.

In another embodiment, the compound is a compound of Formula IV or asalt thereof,

wherein

R¹ is selected from the group consisting of hydrogen, halogen, alkyl,alkoxy, haloalkyl, and haloalkoxy;

R² is selected from the group consisting of aryl and heteroaryl, each ofwhich may be optionally independently substituted with one or moresubstituents selected from the group consisting of halogen, OH, CN,alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, C₁ to C₄ hydroxyalkyl,N(R⁷R⁸), and NR⁹C(O)R¹⁰, wherein R⁷ and R⁸ are each independentlyselected from the group consisting of hydrogen and alkyl, and wherein R⁹is selected from the group consisting of hydrogen and alkyl and R¹⁰ isalkyl;

R³, R⁴, R⁵, and R⁶ are each independently selected from the groupconsisting of hydrogen, halogen, OH, alkyl, alkoxy, haloalkyl,haloalkoxy, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), NR⁹C(O)R¹⁰, and C(O)R¹¹,wherein R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen and alkyl, and wherein R⁹ is selected from thegroup consisting of hydrogen and alkyl and R¹⁰ and R¹¹ are alkyl; and

Z is selected from the group consisting of aryl and heteroaryl, each ofwhich may be optionally independently substituted with one or moresubstituents selected from the group consisting of halogen, alkyl,alkoxy, haloalkyl, and haloalkoxy, C₁ to C₄ hydroxyalkyl, CN, and C(H)O.

In some embodiments, R² is selected from the group consisting of aryland heteroaryl, each of which may be optionally independentlysubstituted with one or more substituents selected from the groupconsisting of halogen, OH, CH₃, OCH₃, CF₃, OCF₃, and CN. For example, insome embodiments, R² is phenyl.

In some embodiments, Z is selected from the group consisting of aryl andheteroaryl, each of which may be optionally independently substitutedwith one or more substituents selected from the group consisting ofhalogen, CH₃, OCH₃, CF₃, OCF₃, CN, and C(H)O.

For example, in some embodiments, Z is selected from the groupconsisting of phenyl and thienyl. In some embodiments, Z is phenyl. Inother embodiments, Z is thienyl.

As used herein, the term “halo” or “halogen” refers to any radical offluorine, chlorine, bromine or iodine.

The term “alkyl” as employed herein, by itself or as part of anothergroup, refers to both straight and branched chain radicals of up to tencarbons. Non-limiting examples of C₁-C₁₀ alkyl groups include methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyland octyl groups. For example, in some embodiments, the term “alkyl” asused herein, by itself or as part of another group, refers to a straightor branched chain radical comprising from one to six carbon atoms.

The term “hydroxyalkyl” as employed herein, refers to both straight andbranched chain alkyl radicals having a hydroxyl substituent. Thehydroxyl substituent can be bound to any carbon of the alkyl chain.Non-limiting examples include CH₂OH, CH₂CH₂OH, CH₂CH(OH)CH₃ andCH₂CH(OH)CH₂CH₃.

The term “haloalkyl” as employed herein, by itself or as part of anothergroup, refers to an alkyl group, as defined herein, substituted with atleast one halogen. Non-limiting examples of haloalkyl groups includetrifluromethyl and 2,2,2-trifluoroethyl.

The term “alkoxy” as employed herein, by itself or as part of anothergroup, refers to an alkyl group, as defined herein, appended to theparent molecular moiety through an oxygen atom. Non-limiting examples ofalkoxy groups include methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, and hexyloxy.

The term “haloalkoxy” as employed herein, by itself or as part ofanother group, refers to an alkoxy group as defined herein, wherein thealkyl moiety of the alkoxy group is further substituted with at leastone halogen. Non-limiting example of haloalkoxy groups includetrifluoromethoxy, and 2,2-dichloroethoxy.

The term “cycloalkyl” as used herein refers to an alkyl group comprisinga closed ring comprising from 3 to 8 carbon atoms. Non-limiting examplesof cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

The term “aryl” as employed herein by itself or as part of another grouprefers to monocyclic, bicyclic or tricyclic aromatic groups containingfrom 6 to 14 carbons in the ring. Common aryl groups include C₆₋₁₄ aryl,preferably C₆₋₁₀ aryl. Typical C₆₋₁₄ aryl groups include phenyl,naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl,biphenylenyl and fluorenyl groups.

The term “heteroaryl” as employed herein refers to groups having 5 to 14ring atoms; 6, 10 or 14 π electrons shared in a cyclic array; andcontaining carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfurheteroactoms. Example heteroaryl groups include thienyl (thiophenyl),benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl),pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl,pyrrolyl, including without limitation 2H-pyrrolyl, imidazolyl,pyrazolyl, pyridyl (pyridinyl), including without limitation 2-pyridyl,3-pyridyl, and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl,quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl,phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl,isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl,1,4-dihydroquinoxaline-2,3-dione, 7-aminoisocoumarin,pyrido[1,2-a]pyrimidin-4-one, pyrazolo[1,5-a]pyrimidinyl, includingwithout limitation pyrazolo[1,5-a]pyrimidin-3-yl,1,2-benzoisoxazol-3-yl, benzimidazolyl, 2-oxindolyl and2-oxobenzimidazolyl. Where the heteroaryl group contains a nitrogen atomin a ring, such nitrogen atom may be in the form of an N-oxide, e.g., apyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.

The term “prodrug of a carboxylic acid” as employed herein refers to anycompound or moiety that can be transformed through chemical or metabolic(enzymatic) processes in vivo to produce carboxylic acid. The prodrug ofa carboxylic acid may be an inactive or less active compound than theparent compound containing the carboxylic acid. A prodrug of acarboxylic acid may have physicochemical properties which result inimproved uptake, distribution or metabolism. In a non-limiting exampleof a prodrug of a carboxylic acid, carboxylic acid can be esterifiedwith a methyl or ethyl group to yield an ester and when the carboxylicacid ester is administered to a biological system (e.g. plant or humansubject) the ester group may be, for example, converted enzymatically,non-enzymatically, oxidatively or hydrolytically to a carboxylate group.Additionally, convertible prodrugs of carboxylic acid moieties include,but are not limited to, substituted and unsubstituted, branched andunbranched lower alkyl ester moieties (methyl ester, ethyl esters,propyl esters, butyl esters, pentyl esters, cyclopentyl esters, hexylesters and cyclohexyl esters), lower alkenyl esters, acyloxy lower alkylesters (e.g. pivaloyloxymethyl ester), aryl esters, and aryl lower alkylesters (e.g. benzyl esters). Alternatively, hydroxyalkyl groups may beoxidized in vivo to a carboxylic acid. Additionally, conventionalprocedures for selection and preparation of suitable prodrug of acarboxylic acid derivatives are known in the art including, for example,as described in “Prodrugs: Challengs and Rewards,” Part 2, Volume 5(2007) pages 3-29 and “Current Methods in Medicinal Chemistry andBiological Physics” Volume 2 (2008) pages 187-214″, which areincorporated herein by reference.

The term “carboxylic acid isostere” as employed herein includes each andall of (1) carboxylic acid isosteres having one or more of thefollowing, the same number of atoms, the same number of valenceelectrons, and exhibiting similar reactive electron shells, volumes andshapes as compared to a carboxylic acid substituent, and (2)non-classical isosteres which fit the broadest definition of isostersand produce biological effects similar to a carboxylic acid substituent.Non-limiting examples of carboxylic acid isosteres include tetrazolyl,aminosulfonyl, acylaminosulfonyl, methyl sulfonylcarbamyl,thiazolidinedionyl, oxazolidinedionyl, oxadiazolonyl, P(O)(OH)₂,P(O)(OH)H, and SO₃H. The concept of carboxylic acid isostere in drugdesign and the properties of several isosters are known in the art anddescribed, for example, by Ballatore at al in ChemMedChem 2013, 8, pages385-395, which is incorporated herein by reference.

Non-limiting examples of species include2-(4-(4-phenylquinolin-2-yl)phenoxy)acetamide of Formula Ia-i, or a saltthereof,

2-(4-(4-phenylquinolin-2-yl)phenoxy)acetic acid of Formula Ia-ii, or asalt thereof,

2-(4-(8-methoxy-4-phenylquinolin-2-yl)phenoxy)acetamide of FormulaIa-iii, or a salt thereof,

2-(4-(8-ethyl-4-phenylquinolin-2-yl)phenoxy)acetamide of Formula Ia-iv,or a salt thereof,

2-(4-(6-chloro-4-phenylquinolin-2-yl)phenoxy)-N-(2-hydroxyethyl)acetamideof Formula Ia-v, or a salt thereof,

2-(5-(3-chloro-4-phenylquinolin-2-yl)thiophen-2-yl)acetamide of FormulaIb-i, or a salt thereof,

2-(5-(3-chloro-4-phenylquinolin-2-yl)thiophen-2-yl)acetic acid ofFormula Ib-ii, or a salt thereof,

2-(5-(4-phenylquinolin-2-yl)thiophen-2-yl)acetamide of Formula Ib-iii,or a salt thereof,

2-(5-(4-phenylquinolin-2-yl)thiophen-2-yl)acetic acid of Formula Ib-iv,or a salt thereof,

2-(5-(8-methoxy-4-phenylquinolin-2-yl)thiophen-2-yl)acetamide of FormulaIb-v, or a salt thereof,

2-(5-(8-ethyl-4-phenylquinolin-2-yl)thiophen-2-yl)acetamide of FormulaIb-vi, or a salt thereof,

2-(4-((1H-tetrazol-5-yl)methoxy)phenyl)-4-phenylquinoline of FormulaIIa-i, or a salt thereof,

((4-(4-phenylquinolin-2-yl)phenoxy)methyl)phosphonic acid of FormulaIIa-ii, or a salt thereof,

((4-(4-phenylquinolin-2-yl)phenoxy)methyl)phosphinic acid of FormulaIIa-iii, or a salt thereof,

(4-(4-phenylquinolin-2-yl)phenoxy)methanesulfonic acid of FormulaIIa-iv, or a salt thereof,

(4-(4-phenylquinolin-2-yl)phenoxy)methanesulfonamide of Formula IIa-v,or a salt thereof,

N-(methyl sulfonyl)-2-(4-(4-phenylquinolin-2-yl)phenoxy)acetamide ofFormula IIa-vi, or a salt thereof,

5-((4-(4-phenylquinolin-2-yl)phenoxy)methyl)thiazolidine-2,4-dione ofFormula IIa-vii, or a salt thereof,

5-((4-(4-phenylquinolin-2-yl)phenoxy)methyl)oxazolidine-2,4-dione ofFormula IIa-viii, or a salt thereof,

3-((4-(4-phenylquinolin-2-yl)phenoxy)methyl)-1,2,4-oxadiazol-5(4H)-oneof Formula IIa-ix, or a salt thereof,

2-(5-((1H-tetrazol-5-yl)methyl)thiophen-2-yl)-4-phenylquinoline ofFormula IIb-i, or a salt thereof,

((5-(4-phenylquinolin-2-yl)thiophen-2-yl)methyl)phosphonic acid ofFormula IIb-ii, or a salt thereof,

((5-(4-phenylquinolin-2-yl)thiophen-2-yl)methyl)phosphonic acid ofFormula IIb-iii, or a salt thereof,

(5-(4-phenylquinolin-2-yl)thiophen-2-yl)methanesulfonic acid of FormulaIIb-iv, or a salt thereof,

(5-(4-phenylquinolin-2-yl)thiophen-2-yl)methanesulfonamide of FormulaIIb-v, or a salt thereof,

N-(methylsulfonyl)-2-(5-(4-phenylquinolin-2-yl)thiophen-2-yl)acetamideof Formula IIb-vi, or a salt thereof,

5-((5-(4-phenylquinolin-2-yl)thiophen-2-yl)methyl)thiazolidine-2,4-dioneof Formula IIb-vii, or a salt thereof,

5-((5-(4-phenylquinolin-2-yl)thiophen-2-yl)methyl)oxazolidine-2,4-dioneof Formula IIb-viii, or a salt thereof,

3-((5-(4-phenylquinolin-2-yl)thiophen-2-yl)methyl)-1,2,4-oxadiazolidin-5-oneof Formula IIb-ix, or a salt thereof,

methyl 2-(4-(4-phenylquinolin-2-yl)phenoxy)acetate of Formula IIc-i, ora salt thereof,

methyl 2-(5-(4-phenylquinolin-2-yl)thiophen-2-yl)acetate of FormulaIId-i, or a salt thereof,

methyl 2-(5-(3-chloro-4-phenylquinolin-2-yl)thiophen-2-yl)acetate ofFormula IId-ii, or a salt thereof,

2-((7-methoxy-4-phenylquinolin-2-yl)thio)propanamide of Formula III-i,or a salt thereof,

2-(4-methoxyphenyl)-4-phenylquinoline of Formula IV-i, or a saltthereof, and

2-(3,4-dimethoxyphenyl)-4-phenylquinoline of Formula IV-ii, or a saltthereof.

Enantiomers

The compounds described herein may be present as a racemic mixture, as amixture of two enantiomers at different ratios, or as a singleenantiomer. Compositions that are enriched with respect to oneenantiomer, or which comprise substantially a single enantionmer, may beprepared using any technique known in the art, including chiralseparation techniques known in the art (e.g., chiral chromatography orasymmetric synthesis).

Compositions

In another aspect, the present disclosure is generally related to acomposition comprising an effective amount of a compound (e.g., acompound of Formula I, Ia, Ib, II, IIa, IIb IIc, IId, III, or IV) asdescribed herein as an ACCase modulator or inhibitor for use inadministration to a plant, a seed, or soil to control fungal pathogens.

For example, the composition may be an aqueous composition.

Generally, the compositions described herein can comprise any adjuvants,excipients, or other desirable components known in the art.

Non-limiting examples of additional ingredients include surfactants,co-surfactants, permeation enhancers, and co-solvents. For example, thecomposition may comprise as SPAN surfactants, TWEEN surfactants, TRITONsurfactants, MAKON surfactants, IGEPAL surfactants, BRIJ surfactants,MORWET surfactants, PLURONIC surfactants, LANEXOL surfactants, ATLOXsurfactants, ATLAS surfactants, SURFYNOL surfactants, TERGITOLsurfactants, DOWFAX surfactants, TOXIMUL surfactants, SILWETsurfactants, SYLGARD surfactants, BREAK THRU surfactants, PHYTOSAN,SOLUPLUS, cyclodextrans, polypropylene glycol, ethyl lactate, methylsoyate/ethyl lactate co-solvent blends (e.g., STEPOSOL), isopropanol,acetone, ethylene glycol, propylene glycol, n-alkylpyrrolidones (e.g.,the AGSOLEX series), a petroleum based-oil (e.g., AROMATIC 200) or amineral oil (e.g., paraffin oil)).

For example, in some embodiments, the composition comprises asurfactant. Non-limiting examples of surfactants include SPAN 20, SPAN40, SPAN 80, SPAN 85, TWEEN 20, TWEEN 40, TWEEN 80, TWEEN 85, TRITON X100, MAKON 10, IGEPAL CO 630, BRU 35, BRU 97, TERGITOL TMN 6, DOWFAX3B2, PHYSAN and TOXIMUL TA 15.

In some embodiments, the composition comprises a co-solvent. Examples ofco-solvents that can be used include ethyl lactate, methyl soyate/ethyllactate co-solvent blends (e.g., STEPOSOL), isopropanol, acetone,1,2-propanediol, n-alkylpyrrolidones (e.g., the AGSOLEX series), apetroleum based-oil (e.g., AROMATIC 200) or a mineral oil (e.g.,paraffin oil)).

In some embodiments, the composition may be formulated, mixed in a tank,combined on a seed by overcoating, or recommended for use with one ormore additional active ingredients on a seed, plant, or soil. Theadditional active ingredient may be, for example, an additionalpesticide. The pesticide may be, for example, an insecticide, afungicide, an herbicide, or an additional nematicide.

Non-limiting examples of insecticides and nematicides includecarbamates, diamides, macrocyclic lactones, neonicotinoids,organophosphates, phenylpyrazoles, pyrethrins, spinosyns, syntheticpyrethroids, tetronic and tetramic acids. In another embodiment,insecticides and nematicides include abamectin, aldicarb, aldoxycarb,bifenthrin, carbofuran, chlorantraniliprole, clothianidin, cyfluthrin,cyhalothrin, cypermethrin, deltamethrin, dinotefuran, emamectin,ethiprole, fenamiphos, fipronil, flubendiamide, fosthiazate,imidacloprid, ivermectin, lambda-cyhalothrin, milbemectin, nitenpyram,oxamyl, permethrin, spinetoram, spinosad, spirodichlofen, spirotetramat,tefluthrin, thiacloprid, thiamethoxam, and thiodicarb.

In some embodiments, the composition comprises an insecticide and/oracaricide that inhibits ACCase activity. Non-limiting examples includetetramic acids such as spirotetramat, and tetronic acids includingspiromesifen and spirodiclofen.

In some embodiments, the composition comprises one or more nematicidalcompounds as described in U.S. Pub. Nos. 2009/0048311 A1 or 2011/028320A1, or WO 2012/030887 A1, the contents of which are herein incorporatedby reference.

For example, in some embodiments, the composition comprises3-phenyl-5(thiophen-2-yl)-1,2,4-oxadiazole.

Non-limiting examples of herbicides include ACCase inhibitors,acetanilides, AHAS modulators or inhibitors, carotenoid biosynthesisinhibitors, EPSPS modulators or inhibitors, glutamine synthetasemodulators or inhibitors, PPO modulators or inhibitors, PS II modulatorsor inhibitors, and synthetic auxins. Non-limiting examples of herbicidesinclude acetochlor, clethodim, dicamba, flumioxazin, fomesafen,glyphosate, glufosinate, mesotrione, quizalofop, saflufenacil,sulcotrione, and 2,4-D.

In one embodiment, an herbicide compound is selected that inhibitsACCase activity. Non-limiting examples include herbicidalaryloxyphenoxypropionates such as chlorazifop, clodinafop, clofop,cyhalofop, diclofop, fenoxaprop, fenoxaprop-P, fenthiaprop, fluazifop,fluazifop-P, haloxyfop, haloxyfop-P, isoxapyrifop, kuicaoxi, metamifop,propaquizafop, quizalofop, quizalofop-P, and trifop, herbicidalcyclohexanediones such as alloxydim, butroxydim, clethodim, cloproxydim,cycloxydim, profoxydim, sethoxydim, tepraloxydim, and tralkoxydim, aswell as the herbicide pinoxaden.

The herbicides cycloxydim and sethoxydim are known to exhibit moderateantifungal activity alone, and, without being bound to a particulartheory, it is believed that the combination of these species with thecompounds described herein may enhance fungal control by the additionalsuppression of ACCase.

The composition may comprise one or more additional fungicides.Non-limiting examples of additional fungicides include aromatichydrocarbons, benzimidazoles, benzothiadiazole, carboxamides, carboxylicacid amides, morpholines, phenylamides, phosphonates, quinine outsideinhibitors (e.g. strobilurins), thiazolidines, thiophanates, thiophenecarboxamides, and triazoles, Particular examples of fungicides includeacibenzolar-S-methyl, azoxystrobin, benalaxyl, bixafen, boscalid,carbendazim, cyproconazole, dimethomorph, epoxiconazole, fluopyram,fluoxastrobin, flutianil, flutolanil, fluxapyroxad, fosetyl-Al,ipconazole, isopyrazam, kresoxim-methyl, mefenoxam, metalaxyl,metconazole, myclobutanil, orysastrobin, penflufen, penthiopyrad,picoxystrobin, propiconazole, prothioconazole, pyraclostrobin, sedaxane,silthiofam, tebuconazole, thifluzamide, thiophanate, tolclofos-methyl,trifloxystrobin, and triticonazole.

In some embodiments, the composition comprises one or more additionalfungicides that modulate or inhibit ACCase activity.

The composition may also comprise one or more additional activesubstances, including biological control agents, microbial extracts,natural products, plant growth activators and/or plant defense agents.Non-limiting examples of biological control agents include bacteria,fungi, beneficial nematodes, and viruses.

For example, in certain embodiments, the biological control agent can bea bacterium of the genus Actinomycetes, Agrobacterium, Arthrobacter,Alcaligenes, Aureobacterium, Azobacter, Beijerinckia, Brevibacillus,Burkholderia, Chromobacterium, Clostridium, Clavibacter, Comamonas,Corynebacterium, Curtobacterium, Enterobacter, Flavobacterium,Gluconobacter, Hydrogenophage, Klebsiella, Methylobacterium,Paenibacillus, Pasteuria, Photorhabdus, Phyllobacterium, Pseudomonas,Rhizobium, Serratia, Sphingobacterium, Stenotrophomonas, Variovax, andXenorhabdus.

In some embodiments, the biological control agent can be a fungus of thegenus Alternaria, Ampelomyces, Aspergillus, Aureobasidium, Beauveria,Colletotrichum, Coniothyrium, Gliocladium, Metarhizium, Muscodor,Paecilomyces, Trichoderma, Typhula, Ulocladium, and Verticillium. Inparticular embodiments the fungus is Beauveria bassiana, Coniothyriumminitans, Gliocladium virens, Muscodor albus, Paecilomyces lilacinus, orTrichoderma polysporum.

In further embodiments, the biological control agents can be plantgrowth activators or plant defense agents including, but not limited toharpin, Reynoutria sachalinensis, jasmonate, lipochitooligosaccharides,and isoflavones.

Methods of Use

ACCase is an essential catalyst for the rate-limiting step of fatty acidbiosynthesis in both eukaryotes and prokaryotes. Without being bound toa particular theory, it is believed that the compounds disclosed hereinmodulate or inhibit ACCase. In one embodiment, a compound (e.g., acompound of Formula I, Ia, Ib, II, IIa, IIb, IIc, IId, III, or IV) asdescribed herein is used as a ACCase modulator. Additionally, compoundsas described herein of Formulas I, Ia, Ib, II, IIa, IIb, IIc, IId, III,or IV are also believed to exhibit control of phytopathogenic fungi, asdescribed herein. In one embodiment, the compounds disclosed herein areadministered to a plant, a seed, or soil in a composition as describedherein to control fungal pathogens, including using the compounds asdescribed herein with any adjuvants, excipients, or other desirablecomponents as described herein or known in the art and formulating,mixing, or combining one or more additional active ingredients. Theadditional active ingredient may be, for example, an additionalpesticide. The pesticide may be, for example, an insecticide, afungicide, an herbicide, or an additional nematicide as described hereinor otherwise known in the art.

The compounds and compositions described herein can be administered toseeds, plants, or the environment of plants (e.g., soil) wherein thecontrol of phytopathogenic fungi is desired. For example, in oneembodiment, the disclosure is generally related to a method ofcontrolling fungal pathogens, the method comprising administering to aplant, a seed or soil a composition comprising an effective amount of acompound as described herein.

Non-limiting examples of plants that may be protected from fungalpathogens in accordance with the methods described herein includemonocotyledon crops such as corn, wheat, barley, rye, rice, sorghum,oat; sugarcane and turf; and dicotyledon crops such as cotton, sugarbeet, peanut, potato, sweet potato, yam, sunflower, soybean, alfalfa,canola, grapes, tobacco; vegetables including Solanaceae vegetables suchas eggplant, tomato, green pepper and pepper; Cucurbitaceae vegetablessuch as cucumber, pumpkin, zucchini, watermelon, melon and squash;Brassicaceae vegetables such as radish, turnip, horseradish, Chinesecabbage, cabbage, leaf mustard, broccoli and cauliflower; Asteraceaevegetables such as artichoke and lettuce; Liliaceae vegetables such asleek, onion, garlic and asparagus; Apiaceae vegetables such as carrot,parsley, celery and parsnip; Chenopodiaceae vegetables such as spinachand chard; Lamiaceae vegetables such as mint and basil; flowers such aspetunia, morning glory, carnation, chrysanthemum and rose; foliageplants; fruit trees such as pome fruits (e.g., apple, pear and Japanesepear), stone fruits (e.g., peach, plum, nectarine, cherry, apricot andprune), citrus (e.g., orange, lemon, lime and grapefruit), tree nuts(e.g., chestnut, pecan, walnut, hazel, almond, pistachio, cashew andmacadamia), berries such as blueberry, cranberry, blackberry, strawberryand raspberry; persimmon; olive; loquat; banana; coffee; palm; coco; theother trees such tea, mulberry, flower trees, and landscape trees (e.g.,ash, birch, dogwood, eucalyptus, ginkgo, lilac, maple, oak, poplar,Formosa sweet gum, sycamore, fir, hemlock fir, needle juniper, pine,spruce, yew).

Non-limiting examples of the plant diseases that may be controlled bythe methods described herein include diseases caused by phytopathogenicfungi (in particular of the classes of Ascomycetes, Deuteromycetes,Oomycetes and Basidiomycetes) such as Magnaporthe grisea, Cochliobolusmiyabeanus, Rhizoctonia solani and Gibberella fujikuroi on rice;Erysiphe graminis, Fusarium graminearum, F. avenacerum, F. culmorum,Microdochium nivale, Puccinia striiformis, P. graminis, P. recondita, P.hordei, Typhula sp., Micronectriella nivalis, Ustilago tritici, U. nuda,Tilletia caries, Pseudocercosporella herpotrichoides, Rhynchosporiumsecalis, Septoria tritici, Leptosphaeria nodorum and Pyrenophora tereson wheat and barley; Diaporthe citri, Elsinoe fawcetti, Penicilliumdigitatum, P. italicum, Phytophthora parasitica and Phytophthoracitrophthora on citrus; Monilinia mali, Valsa ceratosperma, Podosphaeraleucotricha, Alternaria alternata apple pathotype, Venturia inaequalis,Colletotrichum acutatum and Phytophtora cactorum on apple; Venturianashicola, V. pirina, Alternaria alternata Japanese pear pathotype,Gymnosporangium haraeanum and Phytophthora cactorum on pear; Moniliniafructicola, Cladosporium carpophilum and Phomopsis sp. on peach; Elsinoeampelina, Glomerella cingulata, Uncinula necator, Phakopsoraampelopsidis, Guignardia bidwellii and Plasmopara viticola on grape;Gloeosporium kaki, Cercospora kaki and Mycosphaerella nawae onpersimmon; Colletotrichum lagenarium, Sphaerotheca fuliginea,Mycosphaerella melonis, Fusarium oxysporum, Pseudoperonospora cubensisand Phytophthora sp. on Cucurbitales vegetables; Alternaria solani,Cladosporium fulvum and Phytophthora infestans on tomato; Phomopsisvexans and Erysiphe cichoracearum on eggplant; Alternaria japonica,Cercosporella brassicae, Plasmodiophora brassicae and Peronosporaparasitica on Brassicaceae vegetables; Puccinia allii and Peronosporadestructor on leek; Cercospora kikuchii, Elsinoe glycines, Diaporthephaseolorum var. sojae, Phakopsora pachyrhizi and Phytophthora sojae onsoybean; Colletotrichum lindemuthianum of kidney bean; Cercosporapersonata, Cercospora arachidicola and Sclerotium rolfsii on peanut;Erysiphe pisi on pea; Alternaria solani, Phytophthora infestans,Phytophthora erythroseptica and Spongospora subterranean f. sp.subterranean on potato; Sphaerotheca humuli and Glomerella cingulata onstrawberry; Exobasidium reticulatum, Elsinoe leucospila, Pestalotiopsissp. and Colletotrichum theae-sinensis on tea; Alternaria longipes,Erysiphe cichoracearum, Colletotrichum tabacum, Peronospora tabacina andPhytophthora nicotianae on tobacco; Cercospora beticola, Thanatephoruscucumeris, and Aphanidermatum cochlioides on sugar beet; Diplocarponrosae, Sphaerotheca pannosa and Peronospora sparsa on rose; Bremialactucae, Septoria chrysanthemi-indici and Puccinia horiana onchrysanthemum and Compositae vegetables; Alternaria brassicicola onradish; Sclerotinia homeocarpa and Rhizoctonia solani on turf;Mycosphaerella fijiensis and Mycosphaerella musicola on banana;Plasmopara halstedii on sunflower; and various diseases on crops causedby Aspergillus spp., Alternaria spp., Cephalosporium spp., Cercosporaspp., Cochliobolus spp., Diaporthe spp., Phomopsis spp., Diplodia spp.,Fusarium spp., Gibberella spp., Helminthosporium spp., Phakopsora spp.,Phytophthora spp., Blumeria spp., Oidium spp., Erysiphe spp., Uncinulaspp., Podosphaera spp., Microsphaera spp., Colletotrichum spp.,Corynespora spp., Peronospora spp., Plasmopara spp., Pythium spp.,Pyrenophora spp., Pythium spp., Rhizoctonia spp., Rhynchosporium spp.,Botryotinia spp., Botrytis spp., Botryosphaeria spp., Sphaerotheca spp.,Septoria spp., Thielaviopsis spp., Typhula spp., Pseudocercosporellaspp., Cochliobolus spp., Gaeumannomyces spp., Mucor spp., Puccinia spp.,Tilletia spp., Ustilago spp., Venturia spp., Gymnosporangium spp.,Claviceps spp., Cladosporium spp., Physalospora spp., Pyricularia spp.,Magnaporthe spp., Rhizopus spp., Monilinia spp., Cladosporium spp.,Curvularia spp., Sclerotinia spp., Sclerotium sp., Corticum spp.,Corticium spp., Phoma spp., Polymyxa spp., and Olpidium spp.

Application to Plants and/or Soil

Generally, the methods described herein can be used to modulate, inhibitor eradicate fungal pathogens as described herein that cause disease onvarious parts of agricultural crop plants (e.g., fruit, blossoms,leaves, stems, tubers, roots) or other useful plants as describedherein. For example, the methods described herein may be used tomodulate, inhibit, and/or control any of the fungal pathogens and/orplant diseases listed above.

For example, the methods described herein may be used to modulate,inhibit or eradicate plant fungal pathogens in vegetable crops, rowcrops, trees, nuts, vines, turf, and ornamental plants.

In some embodiments, a composition comprising a compound as describedherein may be supplied to a plant exogenously. The composition may beapplied to the plant and/or the surrounding soil through sprays, drips,and/or other forms of liquid application.

The compounds described herein may penetrate the plant through the rootsvia the soil (systemic action); by drenching the locus of the plant witha liquid composition; or by applying the compounds in solid form to thesoil, e.g. in granular form (soil application).

As used herein, the term “locus” broadly encompasses the fields on whichthe treated plants are growing, or where the seeds of cultivated plantsare sown, or the place where the seed will be placed into the soil.

For example, in some embodiments, a composition is applied to a plant,including plant leaves, shoots, roots or seeds. In one embodiment, acomposition comprising a compound as described herein applied to afoliar surface of a plant. Foliar applications may require 50 to 500 gper hectare of a compound as described herein.

As used herein, the term “foliar surface” broadly refers to any greenportion of a plant having surface that may permit absorption of silicon,including petioles, stipules, stems, bracts, flowerbuds, and leaves.Absorption commonly occurs at the site of application on a foliarsurface, but in some cases, the applied composition may run down toother areas and be absorbed there.

The compositions described herein can be applied to the foliar surfacesof the plant using any conventional system for applying liquids to afoliar surface. For example, in some embodiments, application byspraying will be found most convenient. Any conventional atomizationmethod can be used to generate spray droplets, including hydraulicnozzles and rotating disk atomizers. In some embodiments, alternativeapplication techniques, including application by brush or by rope-wick,may be utilized.

In some embodiments, a composition comprising a compound as describedherein is directly applied to the soil surrounding the root zone of aplant. Soil applications may require 0.1 to 5 kg per hectare of acompound as described herein on a broadcast basis (rate per treated areaif broadcast or banded).

For example, in some embodiments, a composition may be applied directlyto the base of the plants or to the soil immediately adjacent to theplants.

In some embodiments, a sufficient quantity of the composition is appliedsuch that it drains through the soil to the root area of the plants.

Generally, application of the composition may be performed using anymethod or apparatus known in the art, including but not limited to handsprayer, mechanical sprinkler, or irrigation, including drip irrigation.

In some embodiments, the composition is applied to plants and/or soilusing a drip irrigation technique. For example, the composition may beapplied through existing drip irrigation systems. This procedure is usedin some embodiments in connection with cotton, strawberries, tomatoes,potatoes, vegetables, and ornamental plants.

In other embodiments, a composition is applied to plants and/or soilusing a drench application. The drench application technique is used insome embodiments in connection with crop plants and turf grasses.

In some embodiments, a composition is applied to soil after planting. Inother embodiments, however, the composition may be applied to soilduring planting, or a treatment composition may be applied to soilbefore planting.

For example, in some embodiments, a composition may be tilled into thesoil or applied in furrow.

In crops of water, such as rice, solid granulates comprising thecompounds described herein may be applied to the flooded field or locusof the crop plants to be treated.

Application to Seeds

One embodiment of the disclosure is generally related to a method ofprotecting a seed, and/or the roots of a plant grown from the seed,against damage by phytopathogenic fungi. The seed treatment methodsdescribed herein may be used to modulate, inhibit, and/or control any ofthe fungal pathogens and/or plant diseases described above. In oneembodiment, the method comprises treating a seed with a compositioncomprising a compound as described herein. As used herein, the term“seed” broadly encompasses plant propagating material such as, tuberscuttings, seedlings, seeds, and germinated or soaked seeds.

In one embodiment, the disclosure relates to a method of administeringto a seed a compound (e.g., a compound of Formula I, Ia, Ib, II, IIa,IIb, IIc, IId, III, or IV) as described to control fungal pathogens in acomposition as described herein, including using the compounds asdescribed herein with the any adjuvants, excipients, or other desirablecomponents as described herein or known in the art and formulating,mixing, or combining one or more additional active ingredients. Theadditional active ingredient may be, for example, an additionalpesticide. The pesticide may be, for example, an insecticide, afungicide, an herbicide, or an additional nematicide as described hereinor otherwise known in the art.

For example, a compound as described herein may be applied to seeds ortubers by impregnating them with a liquid seed treatment compositioncomprising a compound described herein, or by coating them with a solidor liquid composition comprising a compound described herein.

Seed treatment methods described herein can be used in connection withany species of plant and/or the seeds thereof as described herein. Insome embodiments, however, the methods are used in connection with seedsof plant species that are agronomically important. In particular, theseeds can be of corn, peanut, canola/rapeseed, soybean, cucurbits,crucifers, cotton, beets, rice, sorghum, sugar beet, wheat, barley, rye,sunflower, tomato, sugarcane, tobacco, oats, as well as other vegetableand leaf crops. In some embodiments, the seed is corn, soybean, orcotton seed. The seed may be a transgenic seed from which a transgenicplant can grow and incorporate a transgenic event that confers, forexample, tolerance to a particular herbicide or combination ofherbicides, insect resistance, increased disease resistance, enhancedtolerance to stress and/or enhanced yield. Transgenic seeds include, butare not limited to, seeds of corn, soybean and cotton.

A seed treatment method may comprise applying a composition to the seedprior to sowing the seed, so that the sowing operation is simplified. Inthis manner, seeds can be treated, for example, at a central locationand then dispersed for planting. This permits the person who plants theseeds to avoid the complexity and effort associated with handling andapplying the compositions, and to merely handle and plant the treatedseeds in a manner that is conventional for regular untreated seeds.

A composition can be applied to seeds by any standard seed treatmentmethodology, including but not limited to mixing in a container (e.g., abottle or bag), mechanical application, tumbling, spraying, immersion,and solid matrix priming. Seed coating methods and apparatus for theirapplication are disclosed in, for example, U.S. Pat. Nos. 5,918,413;5,891,246; 5,554,445; 5,389,399; 5,107,787; 5,080,925; 4,759,945 and4,465,017, among others. Any conventional active or inert material canbe used for contacting seeds with the composition, such as conventionalfilm-coating materials including but not limited to water-based filmcoating materials.

For example, in one embodiment, a composition can be introduced onto orinto a seed by use of solid matrix priming. For example, a quantity ofthe composition can be mixed with a solid matrix material and then theseed can be placed into contact with the solid matrix material for aperiod to allow the composition to be introduced to the seed. The seedcan then optionally be separated from the solid matrix material andstored or used, or the mixture of solid matrix material plus seed can bestored or planted directly. Non-limiting examples of solid matrixmaterials which are useful include polyacrylamide, starch, clay, silica,alumina, soil, sand, polyurea, polyacrylate, or any other materialcapable of absorbing or adsorbing the composition for a time andreleasing the active compound of the composition into or onto the seed.It is useful to make sure that the active compound and the solid matrixmaterial are compatible with each other. For example, the solid matrixmaterial should be chosen so that it can release the active compound ata reasonable rate, for example over a period of minutes, hours, days, orweeks.

Imbibition is another method of treating seed with the composition. Forexample, a plant seed can be directly immersed for a period of time inthe composition. During the period that the seed is immersed, the seedtakes up, or imbibes, a portion of the composition. Optionally, themixture of plant seed and the composition can be agitated, for exampleby shaking, rolling, tumbling, or other means. After imbibition, theseed can be separated from the composition and optionally dried, forexample by patting or air drying.

A composition may be applied to the seeds using conventional coatingtechniques and machines, such as fluidized bed techniques, the rollermill method, rotostatic seed treaters, and drum coaters. Other methods,such as spouted beds may also be useful. The seeds may be pre-sizedbefore coating. After coating, the seeds may be dried and thentransferred to a sizing machine for sizing. Such procedures aregenerally known in the art.

If a composition is applied to the seed in the form of a coating, theseeds can be coated using a variety of methods known in the art. Forexample, the coating process can comprise spraying the composition ontothe seed while agitating the seed in an appropriate piece of equipmentsuch as a tumbler or a pan granulator.

In one embodiment, when coating seed on a large scale (for example acommercial scale), the seed coating may be applied using a continuousprocess. For example, seed may be introduced into the treatmentequipment (such as a tumbler, a mixer, or a pan granulator) either byweight or by flow rate. The amount of composition that is introducedinto the treatment equipment can vary depending on the seed weight to becoated, surface area of the seed, the concentration of the fungicideand/or other active ingredients in the composition, the desiredconcentration on the finished seed, and the like. A composition can beapplied to the seed by a variety of means, for example by a spray nozzleor revolving disc. The amount of liquid may be determined by the assayof the formulation and the required rate of active ingredient necessaryfor efficacy. As the seed falls into the treatment equipment the seedcan be treated (for example by misting or spraying with the composition)and passed through the treater under continual movement/tumbling whereit can be coated evenly and dried before storage or use.

In another embodiment, the seed coating may be applied using a batchprocess. For example, a known weight of seeds can be introduced into thetreatment equipment (such as a tumbler, a mixer, or a pan granulator). Aknown volume of the composition can be introduced into the treatmentequipment at a rate that allows the composition to be applied evenlyover the seeds. During the application, the seed can be mixed, forexample by spinning or tumbling. The seed can optionally be dried orpartially dried during the tumbling operation. After complete coating,the treated sample can be removed to an area for further drying oradditional processing, use, or storage.

In an alternative embodiment, the seed coating may be applied using asemi-batch process that incorporates features from each of the batchprocess and continuous process embodiments set forth above.

In still another embodiment, seeds can be coated in laboratory sizecommercial treatment equipment such as a tumbler, a mixer, or a pangranulator by introducing a known weight of seeds in the treater, addingthe desired amount of the composition, tumbling or spinning the seed andplacing it on a tray to thoroughly dry.

In another embodiment, seeds can also be coated by placing the knownamount of seed into a narrow neck bottle or receptacle with a lid. Whiletumbling, the desired amount of the composition can be added to thereceptacle. The seed is tumbled until it is coated with the composition.After coating, the seed can optionally be dried, for example on a tray.

In some embodiments, the treated seeds may also be enveloped with a filmovercoating to protect the fungicidal coating. Such overcoatings areknown in the art and may be applied using conventional fluidized bed anddrum film coating techniques. The overcoatings may be applied to seedsthat have been treated with any of the seed treatment techniquesdescribed above, including but not limited to solid matrix priming,imbibition, coating, and spraying, or by any other seed treatmenttechnique known in the art.

Treated Seeds

In one embodiment the disclosure is generally related to a seed that hasbeen treated with a composition as described herein comprising acompound (e.g., a compound of Formula I, Ia, Ib, II, IIa, IIb, IIc, IId,III, or IV) as described herein. In some embodiments, the seed has beentreated with the composition using one of the seed treatment methods setforth above, including but not limited to solid matrix priming,imbibition, coating, and spraying. The treated seed may be of any plantspecies, as described above. In other embodiments, a seed is treatedwith a composition as described herein, including formulating, mixing ina seed treater tank, or combining on a seed by overcoating one or moreadditional active ingredients. The additional active ingredient may be,for example, an additional pesticide. The pesticide may be, for example,an insecticide, a fungicide, an herbicide, or an additional nematicideas described herein.

The amount of a compound present on a treated seed sufficient to protectthe seed, and/or the roots of a plant grown from the seed, againstdamage by phytopathogenic fungi can be readily determined by one ofordinary skill in the art. In an embodiment, treated seeds comprise acompound of Formula I, Ia, Ib, II, IIa, IIb, IIc, IId, III, or IV in anamount of at least about 0.005 mg/seed. In another embodiment, treatedseeds comprise a compound of Formula I, Ia, Ib, II, IIa, IIb, IIc, IId,III, or IV in an amount of from about 0.005 to about 2 mg/seed, or fromabout 0.005 to about 1 mg/seed.

Having described the disclosure in detail, it will be apparent thatmodifications and variations are possible without departing from thescope of the claims.

Administration

In some embodiments, a compound (e.g., a compound of Formula I, Ia, Ib,II, IIa, IIb, IIc, IId, III, or IV) as described herein is used as aACCase modulator. For example, in some embodiments, the presentdisclosure is directed to a method of modulating acetyl-CoA carboxylase(ACCase) in a biological organisim, wherein the method comprisesadministering to the biological organism a composition comprising aneffective amount of a compound.

In some embodiments, the biological organism is an animal. For example,in some embodiments, the biological organism is a warm-blooded animal.In some embodiments, the biological organism is a mammal, including, forexample, humans.

A compound described herein may generally be formulated in a compositioncomprising one or more biologically acceptable excipients and,optionally, another pharmaceutically active agent known to those skilledin the art.

Any suitable dosage may be administered. The compound or salt thereofchosen for a particular application, the carrier and the amount willvary widely depending on the species of the warm blooded animal or humanor the particular disease condition being treated, and depending uponthe effective modulatory concentrations observed in trial studies. Thedosage administered will, of course, vary depending upon known factors,such as the pharmacodynamic characteristics of the particular compoundor salt thereof and its mode and route of administration; the age,health, or weight of the subject; the nature and extent of symptoms; themetabolic characteristics of the composition and patient, the kind ofconcurrent treatment; the frequency of treatment; or the effect desired.

A dosage unit may comprise a single compound, or mixtures thereof, withother compounds. The dosage unit may comprise diluents, extenders,carriers, liposomes, or the like. The unit may be in solid or gel formsuch as pills, tablets, capsules and the like or in liquid form suitablefor oral, rectal, topical, intravenous injection or parenteraladministration or injection into or around the treatment site.

EXAMPLES

The following non-limiting examples are provided for furtherillustration.

Example 1: ACCase Enzymatic Assay

Ustilago maydis acetyl CoA carboxylase (ACCase) was cloned, expressed,and purified as described (Weatherly et al, Biochem. J., 2004) and thetest compounds were tested in a 96-well plate format. Primary in vitroscreening consisted of obtaining dose response data at 100, 33, 10, and1 μM inhibitor. Actives in the primary screen were re-tested toestablish IC50 values.

Direct detection of the conversion of acetyl CoA to malonyl CoA byACCase was not feasible, but during this process ATP is converted to ADPwhich allowed for detection through a standard reaction coupling withADP recycling to the oxidation of NADH. Thus, ACCase activity wasmeasured via kinetic OD340 measurements of the conversion of NADH to NADin a coupled reaction involving the conversion of phosphoenolpyruvate(PEP) to lactate.

The complete 200 ul reaction mixture contained 52.5 mM HEPES (pH8),2.625 mM MgCl₂, 1 mM ATP, 0.525 mM DTT, 11 mM NaHCO₃, 1% DMSO with orwithout inhibitor, lx pyruvate kinase/lactate dehydrogenase (PK/LDH),0.3 mM NADH, 0.5 mM PEP, and 5 μg ACCase. The reactions were incubatedat 30° C. for 10 minutes and then initiated by the addition of 0.33 mMacetyl CoA. The initiated reactions were read immediately via platereader at OD340 and kinetic readings were acquired every 20 s for 15minutes while keeping the temperature at 30° C.

A slope of the kinetic curve was determined by using the 2 to 7 minutedata which was then calculated as percent inhibition relative to the noinhibitor control.

The primary screens were conducted in duplicate and the IC50's conductedin triplicate. Averages were reported along with standard deviationcalculation to generate error bars.

Each plate contained its own controls and consisted of a DMSO onlycontrol, 5-fold titration series of soraphen from 2 μM to 3.2 nM, and anADP coupled reaction control.

In order to effectively screen out non-specific modulators of pyruvatekinase and lactate dehydrogenase (the coupled portion of the reaction),a PK/LDH inhibition test was developed. The complete 200 μl reactionmixture contained 52.5 mM HEPES (pH8), 2.625 mM MgCl₂, 0.525 mM DTT, 11mM NaHCO₃, 1% DMSO with or without inhibitor, lx pyruvate kinase/lactatedehydrogenase (PK/LDH), 0.3 mM NADH, and 0.5 mM PEP. The reactions wereincubated at 30° C. for 10 minutes and then initiated by the addition of66 μM ADP. The initiated reactions were read immediately via platereader at OD340 and kinetic readings were acquired every 20 s for 15minutes while remaining at 30° C.

A slope of the kinetic curve was determined by using the 2 to 7 minutedata which was then calculated as percent inhibition relative to the noinhibitor control. Those compounds which had no significant PK/LDHinhibition at or above the 1050 in the ACCase assay, were considered tobe valid modulators of only ACCase. The 1050 data for compoundsdisclosed herein is shown in Table 1A below.

TABLE 1A ACCase Inhibitory Activity IC50 Formula Name Structure (μM)Ia-i 2-(4-(4-phenylquinolin-2- yl)phenoxy)acetamide

0.515 Ia-ii 2-(4-(4-phenylquinolin-2- yl)phenoxy)acetic acid

0.165 Ia-iii 2-(4-(8-methoxy-4- phenylquinolin-2- yl)phenoxy)acetamide

0.549 Ia-iv 2-(4-(8-ethyl-4- phenylquinolin-2- yl)phenoxy)acetamide

8.154 Ia-v 2-(4-(6-chloro-4- phenylquinolin-2- yl)phenoxy)-N-(2-hydroxyethyl)acetamide

13.0 Ib-i 2-(5-(3-chloro-4- phenylquinolin-2- yl)thiophen-2-yl)acetamide

1.32 Ib-ii 2-(5-(3-chloro-4- phenylquinolin-2- yl)thiophen-2-yl)aceticacid

0.110 Ib-iii 2-(5-(4-phenylquinolin-2- yl)thiophen-2-yl)acetamide

8.176 Ib-iv 2-(5-(4-phenylquinolin-2- yl)thiophen-2-yl)acetic acid

0.145 Ib-v 2-(5-(8-methoxy-4- phenylquinolin-2-yl)thiophen-2-yl)acetamide

4.211 Ib-vi 2-(5-(8-ethyl-4- phenylquinolin-2-yl)thiophen-2-yl)acetamide

9.583 IId-i methyl 2-(5-(4- phenylquinolin-2- yl)thiophen-2-yl)acetate

11.97 III-i 2-((7-methoxy-4- phenylquinolin-2- yl)thio)propanamide

8.8 IV-i 2-(4-methoxyphenyl)-4- phenylquinoline

21.16 IV-ii 2-(3,4-dimethoxyphenyl)-4- phenylquinoline

7.82 Soraphen 0.0458^(a) ^(a)IC50 values are a result of two or moreexperiments

Example 2: Fungal Growth Inhibition Assay

Spores were isolated from previously sub-cultured plates of Botrytiscinerea, Phytophthora capsici, Fusarium mondiforme, Fusariumviguliforme, Collectotrichum graminicola, and Diplodia maydis. Allspores were filtered and collected in a sterile glass bowl to isolatethe spores from the mycelia. The isolation and sub-culture platecondition for each pathogen is described below.

Spore isolation for B. cinerea: A 2-3 week old V8 (17%)+CaCO₃ (3 g/L)+20g agar plate was removed from room temperature and the mycelia weretreated with 5-10 ml of filter sterilized Triton X 100 (0.05%). Themycelia were scraped to re-suspend the spores. The spores were thencollected in a sterile filter bowl containing a fluted piece of filterpaper and poured into a conical tube.

Spore isolation for F. moniliforme: A 1 week old PDA (potato dextroseagar, pre-mix) plate was removed from 26° C. incubator with a light/dark12 hour cycle and the mycelia were treated with 5-10 ml of filtersterilized Triton X 100 (0.05%). The mycelia were scraped to re-suspendthe spores. The spores were then collected in a sterile filter bowlcontaining a fluted piece of filter paper.

Spore isolation for C. graminicola: A 1-2 week old oatmeal agar(pre-mix) plate was removed from 26° C. incubator with a light/dark 12hour cycle and the mycelia were treated with 10-15 ml of filtersterilized distilled water. The mycelia were scraped to re-suspend thespores. The spores were then collected in a sterile filter bowlcontaining a piece of sterile cheesecloth and poured into a conicaltube.

Spore isolation for F. virguliforme: A 2-3 week old PDA (pre-mix) platecontaining cefotaxime (100 mg/L) and kanamycin (50 mg/L) was removedfrom 26° C. incubator with a light/dark 12 hour cycle and the myceliawere treated with 5-10 ml of filter sterilized distilled water. Themycelia were scraped to re-suspend the spores. The spores were thencollected in a sterile filter bowl containing a fluted piece of filterpaper and poured into a conical tube.

Spore isolation for D. maydis: A 3-4 week old PDA (pre-mix) plate wasremoved from 26° C. incubator with a light/dark 12 hour cycle and themycelia were treated with 6-7 ml of sterile distilled water, scrapedinto a sterile petri dish, and smashed to open the pycnidia. The sporeswere then collected in a sterile filter bowl containing a fluted pieceof filter paper and poured into a conical tube.

Spore isolation for P. capsici: Three to five days prior to the assay a2-3 week old V8 (17%)+CaCO₃ (3 g/L)+20 g agar plate was removed from adark 25° C. incubator and cut up into small chunks. One plate wasseparated into two deep well plates and rinsed with sterile distilledwater three times. The cut up pieces were incubated under light in asterile filter hood with 25 ml of sterile distilled water. On the day ofthe assay the water was removed and 5-7 ml of fresh sterile distilledwater was added. One plate was incubated at 4° C. for 45-60 minutes andthen placed at room temperature for about 45-60 minutes. The spores werecollected in a sterile filter bowl containing a fluted piece of filterpaper. The spores were vortexed in a conical tube for 30-60 seconds toremove the flagella of the zoospores after isolation.

After spore isolation, pathogen spores were counted on a hemocytometerto calculate the spores/ml. In 17% V8 liquid media containing 3 g/LCaCO₃, isolated spores were diluted to individual concentrations basedon the growth curves at 48 hours of each pathogen. The sporeconcentrations for each pathogen were as follows: B. cinerea—10,000sp/ml; P. capsici—300 sp/ml; F. monliforme—500 sp/ml; F.virguliforme—500 sp/ml; C. graminicola—3,000 sp/ml; and D. maydis—3,000sp/ml.

Chemistry stocks were dissolved in DMSO at 2.5 mg/ml. Chemistry wasdiluted in a 96-well stock plate in five-fold dilutions to obtain afinal concentration of 50, 10, and 2 ppm in vitro. The finalconcentration of the positive control after the five-fold dilutions wasas follows: soraphen—0.5, 0.1, and 0.02 ppm. Negative controls on eachplate included 2% DMSO, water containing spores and media, and a blankfor background subtraction.

In a 96-well plate the spore solution, chemistries, and controls werecombined to make the final solution concentrations mentioned above. Uponaddition of the chemistry, an OD600 reading was done to assess chemicalprecipitation. The 96-well plates were incubated in plastic tubscontaining wet paper towels under the following conditions, 25° C. inthe dark for P. capsici and B. cinerea or 26° C. with light/dark cyclefor C. graminicola, D. maydis, F. virguliforme, F. monliforme. Platereadings were repeated at 24 and 48 hrs. Visual ratings were performedat 24 and 48 hrs to check for precipitation and confirm efficacy. Visualand OD600 ratings of the chemistry at 48 hours were compared to the 2%DMSO control to determine the percent of pathogen growth inhibition.

Fungal growth inhibition for compounds disclosed herein against severalfungal species is shown in Table 2A through 2F.

TABLE 2A Fungal Growth Inhibition of Collectotrichum graminicola C.graminicola % growth inhibition at 48 h Formula 50 ppm 10 ppm 2 ppm Ib-i51 44 Ib-ii 78 67 0 Ib-iii 81 98 31 Ib-iv 97 53 0 IId-i 79 32 6 IV-i 2235 IV-ii 41 34

TABLE 2B Fungal Growth Inhibition of Diplodia maydis D. maydis % growthinhibition at 48 h Formula 50 ppm 10 ppm 2 ppm Ib-ii 70 55 Ib-iv 89 45 8IIc-i 44 12 IId-i 26 16 IId-ii 30 26 IV-i 44 21 IV-ii 34 26

TABLE 2C Fungal Growth Inhibition of Fusarium virguliforme F.virguliforme % growth inhibition at 48 h Formula 50 ppm 10 ppm 2 ppmIb-i 31 43 Ib-iv 29 4 Ib-ii 41 31 IId-ii 34 44

TABLE 2D Fungal Growth Inhibition of Botrytis cinerea B. cinerea %growth inhibition at 48 h Formula 50 ppm 10 ppm 2 ppm Ib-iv 42 1 0

TABLE 2E Fungal Growth Inhibition of Phytophthora capsici P. capsici %growth inhibition at 48 h Formula 50 ppm 10 ppm 2 ppm Ib-ii 49 31 18Ib-iv 80 11 0

TABLE 2F Fungal Growth Inhibition of Fusarium moniloforme P. capsici %growth inhibition at 48 h Formula 50 ppm 10 ppm 2 ppm Ib-ii 45 39 Ib-iv36 31 17

Example 3: Yeast Growth Inhibition Assay

Yeast cells (Ade2 strain) were grown in liquid YPD (1% yeast extract, 2%peptone, 2% dextrose) for 16 hours at 30° C. from previouslysub-cultured plates of Saccharomyces cerevisiae. The OD600 of theovernight culture was checked via spectrophotometer and diluted to aconcentration of 2×10⁴ cells/ml.

Chemistry stocks were dissolved in DMSO to a concentration of 10 mM.Chemistry stocks were further diluted in a 96-well stock plate to obtainfinal concentrations of 100, 33, 10 and 1 μM in 1% DMSO. The finalconcentrations of the soraphen positive control were 400, 40, and 3.2nM. The negative controls on each plate included a backgroundsubtraction control containing yeast and 1% DMSO (without chemistry) anda second contamination control containing YPD (with no yeast) and 1%DMSO (without chemistry).

98 μl liquid YPD was added to 2 μl diluted stock of DMSO per well andmixed thoroughly. After mixing, 100 μl of the diluted yeast solution wasadded to bring the final yeast concentration to 1×10⁴ cells/ml or 2000cells per well. An initial spectrophotometric reading at OD600 wasconducted on the entire plate and served as the 0 hours time point usedto subtract any background. The plate was then incubated for 24 h at 30°C. with mild shaking. At the 24 h time point all wells of the plate werere-suspended by pipette to yield a uniform suspension, then read againat OD600. The OD600 reading at 0 hours (background) was subtracted fromthe 24 h OD600 reading and all wells were compared to the negativecontrol and subtracted from 100 to determine the percent inhibition. Allexperiments were conducted in triplicate. Averages were reported alongwith standard deviation calculation to generate error bars. Each platecontained its own controls and consisted of inoculated+DMSO,non-inoculated+DMSO, and a titration series of soraphen at 400, 40, and3.2 nM. The results of growth inhibition for Saccharomyces cerevisiaeare reported in Table 2F below.

TABLE 3 Growth Inhibition of Saccharomyces cerevisiae S. cerevisiae %growth inhibition at 48 h Formula 100 μM 33.3 μM 11.1 μM 3.7 μM Ib-ii 7955 0 0 Ib-iii 99 57 14 0 Ib-iv 99 15 0 0

Description of Synthesis

The compounds of Formulas I, Ia, Ib, II, IIa, IIb, IIc, IId, III, and IVmay be prepared using methods known to those skilled in the art.

Example 4: Description of Synthesis of Compounds of Formula Ia

For example, the compounds of Formula Ia can be prepared as set forth inScheme 1 below. More particularly, the optionally substituted2-aminobenzophenone 1 may be reacted with 4-hydroxyacetophenone in thepresence of citric acid at 120° C. to yield the desired4-phenylquinoline derivative 3. Alkylation of the compound 3 withchloroacetamide 4 in the presence of potassium carbonate in acetoneaffords the desired compound of the Formula Ia where Y is NH₂, X is O,and susbtituents R³ to R⁶ are as defined with respect to Formula Iaabove.

The 2-aminobenzophenone 1 described above can be prepared according tothe general synthetic route depicted in Scheme 2. The optionallysubstituted 2-aminobenzoic acid 2 is cyclized to correspondingbenzoxazine 3 by heating in acetic anhydride. Then, the compound 3 isreacted with phenylmagnesium bromide to give the corresponding N-acetyl2-amino benzophenone which is subsequently tretaed with 6NHCl in ethanolto remove the acetyl group and yield the desired 2-aminobenzophenone 1.

Alternatively, the compounds of Formula Ia may be prepared using thegeneral procedure illustrated in Scheme 3, below. More particularly,preparation of a 4-phenylquinoline 3 may be accomplished using aprocedure similar to that described in Scheme 1, above. In the nextstep, alkylation may be carried out with methyl α-bromoacetate 4 toafford the corresponding methyl ester. The saponification of the methylester 5 with 1 NaOH in a mixture of THF and MeOH yields thecorresponding quinolinylphenoxyacetic acid 6, wherein substituents R³ toR⁶ may be selected as defined above with regard to Formula Ia.

Example 5: Description of Synthesis of Compounds of Formula Ib

The compounds of Formula Ib may be prepared as generally set forth inScheme 4 below. More particularly, the optionally substituted2-aminobenzophenone 1 may be reacted with 2-acetyl-heteroaryl-acetamide2b in the presence of citric acid at 120° C. to yield the desiredcompound 3 of Formula Ib. Susbtituents E and R³ to R⁶ may be selected asdefined with respect to Formula Ib above.

The required acetyl-heteroaryl acetic acid derivative 2b may beprepared, for example, as generally illustrated in Scheme 5 below.

Alternatively, the compounds of Formula Ib may be prepared as generallyillustrated in Scheme 6 below. More particularly, preparation of the4-phenylquinoline derivative 3 may be accomplished by reacting of theoptionally substituted 2-aminobenzophenone 1 with methyl2-acetyl-heteroaryl-acetatate 2b in the presence of citric acid at 120°C. The saponification of the methyl ester 3 with 1 NaOH in a mixture ofTHF and MeOH yields the corresponding acid 4. Substituents E and R³ toR⁶ may be selected as defined with respect to Formula Ib above.

In a further alternative, the compounds of Formula Ib may be prepared asgenerally illustrated in Scheme 7 below. More particularly, preparationof the 4-phenylquinoline derivative 3 may be accomplished by reacting ofthe optionally substituted 2-aminobenzophenone 1 with2-chloroacetyl-heteroaryl-acetate 2c in the presence of trimethylsilylchloride (TMS-Cl). The saponification of the methyl ester 3 with 1N NaOHin a mixture of THF and MeOH yields the corresponding acid 4.Alternatively, ammonolysis of the ester 3 with NH₃ in MeOH yields thecorresponding amide 5. Substituents E and R³ to R⁶ may be selected asdefined with respect to Formula Ib above.

Example 6: Description of Synthesis of Compounds of Formula IIa

The compounds of Formula IIa may be prepared as generally set forth inScheme 8 below. More particularly, the optionally substituted2-aminobenzophenone 1 may be reacted with 4-hydroxyacetophenone in thepresence of citric acid at 120° C. to yield the desired4-phenylquinoline derivative 3. The intermediate 3 is then combined withbromoacetonitrile 4 to form the corresponding nitrile 5, which issubseqenetly converted to the corresponding tetrazole 5 with sodiumazide in the presence of ammonium chloride in N,N-dimethylformamide(DMF). Substituents E and R³ to R⁶ may be selected as defined withrespect to Formula IIa above.

Example 6: Description of Synthesis of Compounds of Formula IIb

The compounds of Formula IIb may be prepared as generally set forth inScheme 9 below. More particularly, the optionally substituted2-aminobenzophenone 1 may be reacted with a 2-(5-acetylaryl)acetonitrile2 to form the acetylnitrile derivative 3, which may be subseqenetlyconverted to the corresponding tetrazole 4 with sodium azide in thepresence of ammonium chloride in N,N-dimethylformamide (DMF).Substituents E and R³ to R⁶ may be selected as defined with respect toFormula IIb above.

Example 7: Preparation of 2-aminobenzophenones

The intermediate compounds (2-amino-3-ethylphenyl)(phenyl)methanone and(2-amino-3-methoxyphenyl)(phenyl)methanone were prepared using theprocedures set forth below.

Preparation of (2-amino-3-ethylphenyl)(phenyl)methanone

A mixture of 2-amino-3-ethylbenzoic acid (2.9 g, 17.6 mmol) and aceticanhydride (10 mL) was refluxed for 3 hours. It was cooled to roomtemperature and the precipitate was filtered off and washed with heptane(50 mL) and dried in vacuo to give8-ethyl-2-methyl-4H-benzo[d][1,3]oxazin-4-one (1.84 g, 9.7 mmol, 55%) asa tan solid. The filtrate was concentrated and the residue was purifiedby automated column chromatography on the ISCO-companion (SiO₂, gradientheptane/ethyl acetate) to give an additional amount of the desiredproduct (560 mg, 3.0 mmol, 17%) as an off-white solid. Total yield: 2.4g, 12.7 mmol, 72%. The ¹H-NMR spectrum was in accordance with thechemical structure.

To a solution of 8-ethyl-2-methyl-4H-benzo[d][1,3]oxazin-4-one (2.4 g,12.7 mmol) in a mixture of benzene (10 mL) and THF (3 mL) a 2.8Msolution of phenylmagnesium bromide in Et₂O (4.0 mL, 11.0 mmol) wasadded slowly. After complete addition the mixture was refluxed for 3hours under a N₂-atmosphere. Then, it was cooled to room temperature and2 M HCl (50 mL) and ethyl acetate (50 mL) were added. The layers wereseparated and the aqueous mixture was extracted with ethyl acetate (25mL). The combined organic layers were washed with 2M aq. NaOH (25 mL)and brine (25 mL) and dried over Na₂SO₄. The solvent was evaporated invacuo to give an orange oil. This was taken up in EtOH (30 mL) and 6MHCl (18 mL). The mixture was refluxed for 2 d and concentrated in vacuo.The residue was taken up in a mixture of 25% aq. NH₃ (25 mL) and ethylacetate (25 mL). The layers were separated and the aqueous layer wasextracted with ethyl acetate (25 mL). The combined organic layers werewashed with brine (25 mL) and dried over Na₂SO₄. The solvent wasevaporated in vacuo. The residue was purified by automated columnchromatography on the ISCO-companion (SiO₂, gradient heptane/ethylacetate) to give (2-amino-3-ethylphenyl)(phenyl)methanone (950 mg, 4.2mmol, yield 35%) as a yellow oil. The ¹H-NMR spectrum was in accordancewith the chemical structure.

Preparation of (2-amino-3-methoxyphenyl)(phenyl)methanone

A mixture of 2-amino-3-methoxybenzoic acid (5.0 g, 29.9 mmol) and aceticanhydride (15 mL) was refluxed for 3 hours. It was cooled to roomtemperature and the precipitate was filtered off and washed with heptane(3×25 mL) and dried in vacuo to give8-methoxy-2-methyl-4H-benzo[d][1,3]oxazin-4-one (4.1 g, 21.4 mmol, yield72%) as a tan solid. ¹H-NMR spectrum was in accordance with the chemicalstructure.

Conversion of 8-Methoxy-2-methyl-4H-benzo[d][1,3]oxazin-4-one (3.1 g,16.2 mmol) with 2.8 M phenylmagnesium bromide in Et₂O (as described forthe corresponding compound in the procedure above) afforded(2-amino-3-methoxyphenyl)(phenyl)methanone with a yield of 32% (1.18 g,5.2 mmol) as a yellow solid. The ¹H-NMR spectrum was in accordance withthe chemical structure.

Example 8: Preparation of 2-(4-(4-phenylquinolin-2-yl)phenoxy)acetamide(Formula Ia-i)

A mixture of 2-aminobenzophenone (197 mg, 1.0 mmol),4′-hydroxyacetophenone (150 mg, 1.1 mmol) and citric acid (96 mg, 0.50mmol) were heated for 8 hours to 100° C. (sandbath). The crude mixturewas taken up in CH₂Cl₂ (1 mL) and submitted to automated columnchromatography on the ISCO-companion (SiO₂, gradient ethylacetate/heptane) to give 4-(4-phenylquinolin-2-yl)phenol with a 50%yield (150 mg, 0.5 mmol) as a white solid. The ¹H-NMR spectrum was inaccordance with the chemical structure.

A mixture of 4-(4-phenylquinolin-2-yl)phenol (150 mg, 0.5 mmol), K₂CO₃(138 mg, 1.0 mmol), a catalytic amount of KI and chloroacetamide (129mg, 0.55 mmol) in acetone was refluxed for 18 hours. The mixture wasfiltered and the filtrate was concentrated in vacuo. The residue wasstirred in ethyl acetate (3 mL), filtered and washed with ethyl acetate(2 ml) and dried in air to give2-(4-(4-phenyl-quinolin-2-yl)phenoxy)acetamide with a 48% yield (85 mg,0.24 mmol, 48%) as an off-white solid with an HPLC purity of 99.5%.LC-MS [M+H] 355 (C₂₃H₁₈N₂O₂+H, expected 355.1). The ¹H-NMR spectrum wasin accordance with the chemical structure.

Example 9: Preparation of 2-(4-(4-phenylquinolin-2-yl)phenoxy)aceticacid (Formula Ia-ii)

A mixture of methyl 2-(4-(4-phenylquinolin-2-yl)phenoxy)acetate(prepared as described in Example 20, below) (74 mg, 0.2 mmol), MeOH (1mL), THF (1 mL) and 2N NaOH (1 mL) was stirred for 6 hours at roomtemperature. TLC-control showed complete conversion and the organicsolvent was removed in vacuo. The pH of the aqueous residue wascautiously adjusted to 7-8 with 1 N HCl. The solid was filtered, washedwith H₂O (3×10 mL) and dried in air to give2-(4-(4-phenylquinolin-2-yl)phenoxy)acetic acid (60 mg, 0.169 mmol, 84%)as a tan solid with an HPLC purity of 98.0%. LC-MS [M+H] 356(C₂₃H₁₇NO₃+H, expected 356.1). The ¹H-NMR spectrum was in accordancewith the chemical structure.

Example 10: Preparation of2-(4-(8-methoxy-4-phenylquinolin-2-yl)phenoxy)acetamide (Formula Ia-iii)

A mixture of (2-amino-3-methoxyphenyl)(phenyl)methanone (93 mg, 0.41mmol), 4′-hydroxyacetophenone (61 mg, 0.45 mmol) and citric acid (39 mg,0.205 mmol) was heated for 18 hours to 120° C. (sandbath). The crudemixture was taken up in ethyl acetate (20 mL) and washed with H₂O (10mL) and brine (10 ml) and dried over Na₂SO₄. The solvent was evaporatedin vacuo and the residue was purified by automated column chromatographyon the ISCO-companion (SiO₂, gradient ethyl acetate/heptane) to give4-(8-methoxy-4-phenylquinolin-2-yl)phenol (64 mg, 0.195 mmol, 48%) as anoff-white solid. The ¹H-NMR spectrum was in accordance with the chemicalstructure.

A mixture of 4-(8-methoxy-4-phenylquinolin-2-yl)phenol (64 mg, 0.195mmol), K₂CO₃ (54 mg, 0.39 mmol), a catalytic amount of KI andchloroacetamide (18 mg, 0.2 mmol) in acetone (10 mL) was refluxed for 18hours. Conversion was complete yet and the same amounts of K₂CO₃ (54 mg,0.39 mmol) and chloroacetamide (18 mg, 0.2 mmol) were added. Reflux wascontinued for 24 hours. The mixture was filtered, the filtrate rinsedwith ethyl acetate (20 mL) and the filtrate was concentrated in vacuo.The residue was purified by automated column chromatography on theISCO-companion (SiO₂, gradient ethyl acetate/heptane) to give2-(4-(8-methoxy-4-phenylquinolin-2-yl)phenoxy)acetamide (28 mg, 0.073mmol, 37%) as an off-white solid with an HPLC purity of 99.8%. LC-MS[M+H] 385 (C₂₄H₂₀N₂O₃+H, expected 385.15). The ¹H-NMR spectrum was inaccordance with the chemical structure.

Example 11: Preparation of2-(4-(8-ethyl-4-phenylquinolin-2-yl)phenoxy)acetamide (Formula Ia-iv)

A mixture of (2-Amino-3-ethylphenyl)(phenyl)methanone (112 mg, 0.5mmol), 4′-hydroxyacetophenone 4 (75 mg, 0.55 mmol) and citric acid (48mg, 0.25 mmol) was heated for 20 hours to 120° C. (sandbath). The crudemixture was taken up in ethyl acetate (20 mL) and washed with sat.NaHCO₃ (10 mL) and brine (10 ml) and dried over Na₂SO₄. The solvent wasevaporated in vacuo and the residue was purified by automated columnchromatography on the ISCO-companion (SiO₂, gradient ethylacetate/heptane) to give 4-(8-ethyl-4-phenylquinolin-2-yl)phenol (68 mg,0.209 mmol, 42%) as a pink solid. The ¹H-NMR spectrum was in accordancewith the chemical structure.

A mixture of 4-(8-Ethyl-4-phenylquinolin-2-yl)phenol (68 mg, 0.209mmol), K₂CO₃ (58 mg, 0.42 mmol), a catalytic amount of KI andchloroacetamide (39 mg, 0.209 mmol) in acetone (10 mL) was refluxed for18 hours. The mixture was filtered, the filtrate rinsed with ethylacetate (20 mL) and the filtrate was concentrated in vacuo to give2-((4-(8-Ethyl-4-phenylquinolin-2-yl)phenoxy)acetamide (34 mg, 0.089mmol, 42%) as an off-white solid with an HPLC purity of 99.8%. LC-MS[M+H] 383.2 (C₂₅H₂₂N₂O₂+H, expected 383.17). The ¹H-NMR spectrum was inaccordance with the chemical structure.

Example 12: Preparation of 2-(5-acetylthiophen-2-yl)acetic acidderivatives

The intermediate compounds methyl 2-(5-acetylthiophen-2-yl)acetate and2-(5-acetylthiophen-2-yl)acetamide were prepared using the proceduresset forth below.

Preparation of methyl 2-(5-acetylthiophen-2-yl)acetate

A solution of methyl 2-(thiophen-2-yl)acetate (12.5 g, 80.0 mmol) inCH₂Cl₂ (300 mL) was cooled to 0° C. Acetyl chloride (5.8 mL, 6.4 g, 81.2mmol) was added, followed by the dropwise addition of SnCl₄ (32.0 mL,71.0 g, 272.0 mmol). After complete addition the mixture was stirred for2 hours at 0° C. and 6M HCl (100 mL) was added. The layers wereseparated and the aqueous layer was extracted with TBME (3×100 mL). Thecombined organic layers were washed with sat. NaHCO₃ (100 mL) and brine(100 mL) and dried over Na₂SO₄. The solvent was evaporated in vacuo togive methyl 2-(5-acetylthiophen-2-yl)acetate (15.0 g, 75.7 mmol, 95%) asa yellow oil, that solidified upon standing. The ¹H-NMR spectrum was inaccordance with the chemical structure.

Preparation of 2-(5-acetylthiophen-2-yl)acetamide

A mixture of methyl 2-(5-acetylthiophen-2-yl)acetate (2.0 g, 10.1 mmol)and conc. NH₃ (10 mL) was stirred at room temperature; additional conc.NH₃ (10 mL) to facilitate stirring, which was continued overnight. Themixture was filtered, the solid was washed with H₂O (3×50 mL) and driedin air to give 2-(5-Acetylthiophen-2-yl)acetamide (1.33 g, 7.3 mmol,72%) as a grey solid. The ¹H-NMR spectrum was in accordance with thechemical structure.

Example 13: Preparation of2-(5-(4-phenylquinolin-2-yl)thiophen-2-yl)acetamide (Formula Ib-iii)

A mixture of 2-aminobenzophenone (200 mg, 0.41 mmol),2-(5-acetylthiophen-2-yl)acetamide (61 mg, 0.33 mmol) and citric acid(96 mg, 0.5 mmol) was heated for 18 hours to 120° C. (sandbath). Thecrude mixture was taken up in ethyl acetate (20 mL) and washed with sat.NaHCO₃ (10 mL) and brine (10 ml) and dried over Na₂SO₄. The solvent wasevaporated in vacuo and the residue was purified by automated columnchromatography on the ISCO-companion (SiO₂, gradient ethylacetate/heptane) to give2-(5-(4-phenylquinolin-2-yl)thiophen-2-yl)acetamide in a 33% yield (37mg, 0.108 mmol, 33%) as an off-white solid with an HPLC purity 99.7%.LC-MS [M+H] 345 (C₂₁H₁₆N₂OS+H, expected 345.1). The ¹H-NMR spectrum wasin accordance with the chemical structure.

Example 14: Preparation of2-(5-(3-chloro-4-phenylquinolin-2-yl)thiophen-2-yl)acetamide (FormulaIb-i)

A mixture of methyl2-(5-(3-chloro-4-phenylquinolin-2-yl)thiophen-2-yl)acetate (prepared asdescribed in Example 17) (66 mg, 0.168 mmol) in 7N NH₃ in MeOH (10 mL)was heated for 18 h to 100° C. in a pressure tube. It was cooled to roomtemperature and the solvent was evaporated in vacuo. The residue waspurified by automated column chromatography on the ISCO-companion (SiO₂,CH₂Cl₂/MeOH) to give the slightly impure product. After stirringovernight in Et₂O (10 ml), the solid was filterd off and dried in air togive 2-(5-(3-chloro-4-phenylquinolin-2-yl)thiophen-2-yl)acetamide (35mg, 0.09 mmol, yield 53%) as an off-white solid with an HPLC purity96.5%. LC-MS [M+H] 379/381 (C₂₁H₁₅ClN₂OS+H, expected 379.1/381.1). The¹H-NMR spectrum was in accordance with the chemical structure.

Example 15: Preparation of2-(5-(4-phenylquinolin-2-yl)thiophen-2-yl)acetic acid (Formula Ib-iv)

A mixture of methyl 2-(5-(4-phenylquinolin-2-yl)thiophen-2-yl)acetate(prepared as described in Example 16) (65 mg, 0.188 mmol), MeOH (1 mL),THF (1 mL) and 2 M NaOH (1 mL) was stirred for 6 hours at roomtemperature. TLC-control showed complete conversion and the organicsolvent was removed in vacuo. The pH of the aqueous residue was adjustedto 6 with 1M HCl. The solid was filtered, washed with H₂O (3×10 mL) anddried in air to give 2-(5-(4-Phenylquinolin-2-yl)thiophen-2-yl)aceticacid (38 mg, 0.11 mmol, yield 58%) as an orange solid with an HPLCpurity 86.4%. LC-MS [M+H] 346.2 (C₂₁H₁₄ClNO₂S+H, expected 346.08). The¹H-NMR spectrum was in accordance with the chemical structure.

Example 16: Preparation of methyl2-(5-(4-phenylquinolin-2-yl)thiophen-2-yl)acetate (Formula IId-i)

A mixture of 2-aminobenzophenone (200 mg, 1.0 mmol), methyl2-(5-acetylthiophen-2-yl)acetate (100 mg, 0.51 mmol) and citric acid (96mg, 0.5 mmol) was heated for 24 hours to 120° C. (sandbath). The crudemixture was taken up in CH₂Cl₂ (2 mL) and submitted to automated columnchromatography on the ISCO-companion (SiO₂, gradient ethylacetate/heptane) to give methyl2-(5-(4-phenylquinolin-2-yl)thiophen-2-yl)acetate (75 mg, 0.209 mmol,yield 41%) as a brown oil with an HPLC purity 95.9%. LC-MS [M+H] 360(C₂₂H₁₇NO₂S+H, expected 360.1). The ¹H-NMR spectrum was in accordancewith the chemical structure.

Example 17: Preparation of methyl2-(5-(3-chloro-4-phenylquinolin-2-yl)thiophen-2-yl)-acetate (FormulaIId-ii)

A mixture of 2-aminobenzophenone (340 mg, 1.72 mmol) and methyl2-(5-(2-chloroacetyl)thiophen-2-yl)acetate (400 mg, 1.72 mmol) in DMF(3.5 mL) was transferred to a pressure-tube. Me₃SiCl (1.09 mL, 934 mg,8.6 mmol) was added and the tube was thoroughly sealed. The mixture washeated for 6 h to 100° C. It was cooled to room temperature and pouredinto H₂O (7 mL). The mixture was sonicated at room temperature for 1 h.Meanwhile, a precipitate was formed. EtOAc (25 mL) was added and thelayers were separated. The organic layer was dried over Na₂SO₄ and thesolvent was removed in vacuo. The residue was purified by automatedcolumn chromatography on the ISCO-companion (SiO₂, gradientheptane/EtOAc) to give methyl2-(5-(3-chloro-4-phenylquinolin-2-yl)thiophen-2-yl)acetate (190 mg, 0.48mmol, yield 28%) as an off-white solid with an HPLC purity of 98.6%.LC-MS [M+H] 394 (C₂₂H₁₆ClNO2S+H, expected 394.1). The ¹H-NMR spectrumwas in accordance with the chemical structure.

Example 18: Preparation of2-(5-(3-chloro-4-phenylquinolin-2-yl)thiophen-2-yl)acetic acid (FormulaIb-ii)

A mixture of methyl2-(5-(3-chloro-4-phenylquinolin-2-yl)thiophen-2-yl)acetate (prepared asdecribed in Example 17) (66 mg, 0.168 mmol) in THF (1 mL), MeOH (1 mL)and 2M NaOH (1 mL) was stirred at room temperature for 3 h. Conversionwas complete according to TLC and the solvent was evaporated in vacuo.The pH of the aqueous residue was adjusted to 6-7 by addition of 1 MHCl. The mixture was concentrated in vacuo and the residue was purifiedby automated column chromatography on the ISCO-companion (SiO₂,CH₂Cl₂/MeOH) to give2-(5-(3-chloro-4-phenylquinolin-2-yl)thiophen-2-yl)acetic acid (30 mg,0.079 mmol, yield 47%) as an off-white solid with an HPLC purity of94.8%. LC-MS [M+H] 380 (C₂₁H₁₄ClNO₂S+H, expected 380.04). The ¹H-NMRspectrum was in accordance with the chemical structure.

Example 19: Preparation of2-(5-(8-methoxy-4-phenylquinolin-2-yl)thiophen-2yl)acetamide (FormulaIb-v)

A mixture of (2-amino-3-methoxyphenyl)(phenyl)methanone (340 mg, 1.5mmol), 2-(5-acetylthiophen-2-yl)acetamide (100 mg, 0.546 mmol) andcitric acid (153 mg, 0.8 mmol) was heated for 2 d to 120° C. (sandbath).The crude mixture was taken up in ethyl acetate (20 mL) and washed withsat. NaHCO₃ (2×10 mL) and dried over Na₂SO₄. The solvent was evaporatedin vacuo and the residue was purified by repeated automated columnchromatography on the ISCO-companion (SiO₂, gradient ethylacetate/heptane) to give2-(5-(8-methoxy-4-phenylquinolin-2-yl)thiophen-2-yl)acetamide (29 mg,0.078 mmol, yield 14%) as an tan solid with an HPLC purity of 96.4%.LC-MS [M+H] 375 (C₂₂H₁₈N2O₂S+H, expected 375.1). The ¹H-NMR spectrum wasin accordance with the chemical structure.

Example 20: Preparation of2-(5-(8-ethyl-4-phenylquinolin-2-yl)thiophen-2-yl)acetamide (FormulaIb-vi)

A mixture of (2-amino-3-ethylphenyl)(phenyl)methanone (112 mg, 0.5mmol), 2-(5-acetylthiophen-2-yl)acetamide (31 mg, 0.17 mmol) and citricacid (48 mg, 0.25 mmol) was heated for 18 hours to 120° C. (sandbath).The crude mixture was taken up in ethyl acetate (20 mL) and washed withsat. NaHCO₃ (10 mL) and brine (10 ml) and dried over Na₂SO₄. The solventwas evaporated in vacuo and the residue was purified by automated columnchromatography on the ISCO-companion (SiO₂, gradient ethylacetate/heptane) to give2-(5-(8-ethyl-4-phenylquinolin-2-yl)thiophen-2-yl)acetamide (28 mg,0.075 mmol, 44%) as a tan solid with an HPLC purity of 98.4%. LC-MS[M+H] 373 (C₂₃H₂₀N₂OS+H, expected 373.13). The ¹H-NMR spectrum was inaccordance with the chemical structure.

Example 21: Preparation of methyl2-(4-(4-phenylquinolin-2-yl)phenoxy)acetate (Formula IIc-i)

A mixture of 2-aminobenzophenone (200 mg, 1.0 mmol),4′-hydroxyacetophenone (150 mg, 1.1 mmol) and citric acid (96 mg, 0.5mmol) was heated for 24 hours to 120° C. (sandbath). The crude mixturewas taken up in CH₂Cl₂ (2 mL): a solid precipitated, which was collectedby filtration. After washing with some CH₂Cl₂ (2×1 mL), it was dried inair to give 4-(4-phenylquinolin-2-yl)phenol (70 mg, 0.23 mmol, 23%) asan off-white solid. The ¹H-NMR spectrum was in accordance with thechemical structure.

A mixture of 4-(4-phenylquinolin-2-yl)phenol (70 mg, 0.236 mmol), K₂CO₃(65 mg, 0.47 mmol) and methyl bromoacetate (45 mL, 72 mg, 0.47 mmol) inacetone (10 mL) was refluxed for 18 hours. The mixture was filtered off,the filtrate was rinsed with ethyl acetate (20 mL) and was concentratedin vacuo to give methyl 2-(4-(4-phenylquinolin-2-yl)phenoxy)acetate (84mg, 0.227 mmol, yield 96%) as an off-white solid with an HPLC purity of97.6%. LC-MS [M+H] 370 (C₂₄H₁₉NO₃+H, expected 370.14). The ¹H-NMRspectrum was in accordance with the chemical structure.

When introducing elements of the present disclosure, the articles “a”,“an”, “the” and “said” are intended to mean that there are one or moreof the elements. The terms “comprising”, “including” and “having” areintended to be inclusive and mean that there may be additional elementsother than the listed elements.

In view of the above, it will be seen that the several objects of theinvention are achieved and other advantageous results attained.

As various changes could be made in the above products and methodswithout departing from the scope of the invention, it is intended thatall matter contained in the above description shall be interpreted asillustrative and not in a limiting sense.

What is claimed is:
 1. A method of controlling fungal pathogens, the method comprising administering to a plant, a seed or soil a composition comprising an effective amount of a compound of Formula I or a salt thereof,

wherein R¹ is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy; R² is selected from the group consisting of aryl and heteroaryl, each of which may be optionally independently substituted with one or more substituents selected from the group consisting of halogen, OH, CN, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), and NR⁹C(O)R¹⁰, wherein R⁹ is selected from the group consisting of hydrogen and alkyl and R¹⁰ is alkyl; R³, R⁴, R⁵, and R⁶ are each independently selected from the group consisting of hydrogen, halogen, OH, alkyl, alkoxy, haloalkyl, haloalkoxy, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), NR⁹C(O)R¹⁰, and C(O)R¹¹, wherein R⁹ is selected from the group consisting of hydrogen and alkyl and R¹⁰ and R¹¹ are alkyl; X is selected from the group consisting of a bond, CH₂, O, S, NH, and N(CH₃); Y is selected from the group consisting of OH, NH₂, N(H)OH, N(CH₃)OH, and N(R⁷R⁸); and Z is selected from the group consisting of aryl and heteroaryl, each of which may be optionally independently substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, C₁ to C₄ hydroxyalkyl, CN, and C(H)O; wherein when R² is substituted with N(R⁷R⁸) or when any one of R³, R⁴, R⁵, and R⁶ is N(R⁷R⁸), R⁷ and R⁹ are each independently selected from the group consisting of hydrogen and alkyl; and when Y is N(R⁷R⁸), R⁷ and R⁹ are each independently selected from the group consisting of hydrogen, alkyl, and hydroxyalkyl.
 2. The method of claim 1 wherein the compound is of Formula Ia or a salt thereof,

wherein R¹ is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy; R³, R⁴, R⁵, and R⁶ are each independently selected from the group consisting of hydrogen, halogen, OH, alkyl, alkoxy, haloalkyl, haloalkoxy, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), NR⁹C(O)R¹⁰, and C(O)R¹¹, wherein R⁹ is selected from the group consisting of hydrogen and alkyl and R¹⁰ and R¹¹ are alkyl; X is selected from the group consisting of CH₂, O, S, NH, and N(CH₃); and Y is selected from the group consisting of OH, NH₂, N(H)OH, N(CH₃)OH, and N(R⁷R⁸); wherein when any one of R³, R⁴, R⁵, and R⁶ is N(R⁷R⁸), R⁷ and R⁸ are each independently selected from the group consisting of hydrogen and alkyl; and when Y is N(R⁷R⁸), R⁷ and R⁸ are each independently selected from the group consisting of hydrogen, alkyl, and hydroxyalkyl.
 3. The method of claim 1 wherein the compound is of Formula Ib or a salt thereof,

wherein R¹ is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy; R³, R⁴, R⁵, and R⁶ are each independently selected from the group consisting of hydrogen, halogen, OH, alkyl, alkoxy, haloalkyl, haloalkoxy, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), NR⁹C(O)R¹⁰, and C(O)R¹¹, wherein R⁹ is selected from the group consisting of hydrogen and alkyl and R¹⁰ and R¹¹ are alkyl; Y is selected from the group consisting of OH, NH₂, N(H)OH, N(CH₃)OH, and N(R⁷R⁸); and E is selected from the group consisting of S, O, and N(CH₃); wherein when any one of R³, R⁴, R⁵, and R⁶ is N(R⁷R⁸), R⁷ and R⁸ are each independently selected from the group consisting of hydrogen and alkyl; and when Y is N(R⁷R⁸), R⁷ and R⁸ are each independently selected from the group consisting of hydrogen, alkyl, and hydroxyalkyl.
 4. The method of claim 1 wherein R² is phenyl.
 5. The method of claim 1 wherein Z is phenyl.
 6. The method of claim 1 wherein R¹ is hydrogen.
 7. The method of claim 1 wherein R¹ is halogen.
 8. The method of claim 1 wherein R³, R⁴, R⁵, and R⁶ are each hydrogen.
 9. The method of claim 1 wherein X is a bond.
 10. The method of claim 1 wherein Y is NH₂.
 11. The method of claim 1 wherein R¹ is selected from the group consisting of hydrogen, halogen, CH₃, OCH₃, CF₃, and OCF₃.
 12. The method of claim 1 wherein R³, R⁴, R⁵, and R⁶ are each independently selected from the group consisting of hydrogen, halogen, OH, CH₃, OCH₃, CF₃, and OCF₃.
 13. The method of claim 1 wherein X is O.
 14. The method of claim 1 wherein Y is OH.
 15. The method of claim 1 wherein Z is thienyl.
 16. The method of claim 1 wherein the method comprises administering the composition to a seed.
 17. A treated seed prepared according to the method of claim
 16. 18. The method of claim 1 wherein the method comprises exogenously administering the composition to a plant.
 19. The method of claim 18 wherein the composition is applied to the foliage of a plant.
 20. The method of claim 18 wherein the method comprises applying the composition to the soil surrounding the root zone of a plant.
 21. A method of modulating acetyl-CoA carboxylase (ACCase) in a biological organism, the method comprising administering to the biological organism a composition comprising an effective amount of a compound of Formula I or a salt thereof,

wherein R¹ is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy; R² is selected from the group consisting of aryl and heteroaryl, each of which may be optionally independently substituted with one or more substituents selected from the group consisting of halogen, OH, CN, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), and NR⁹C(O)R¹⁰, wherein R⁹ is selected from the group consisting of hydrogen and alkyl and R¹⁰ is alkyl; R³, R⁴, R⁵, and R⁶ are each independently selected from the group consisting of hydrogen, halogen, OH, alkyl, alkoxy, haloalkyl, haloalkoxy, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), NR⁹C(O)R¹⁰, and C(O)R¹¹, wherein R⁹ is selected from the group consisting of hydrogen and alkyl and R¹⁰ and R¹¹ are alkyl; X is selected from the group consisting of a bond, CH₂, O, S, NH, and N(CH₃); Y is selected from the group consisting of OH, NH₂, N(H)OH, N(CH₃)OH, and N(R⁷R⁸); and Z is selected from the group consisting of aryl and heteroaryl, each of which may be optionally independently substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, C₁ to C₄ hydroxyalkyl, CN, and C(H)O; wherein when R² is substituted with N(R⁷R⁸) or when any one of R³, R⁴, R⁵, and R⁶ is N(R⁷R⁸), R⁷ and R⁸ are each independently selected from the group consisting of hydrogen and alkyl; and when Y is N(R⁷R⁸), R⁷ and R⁸ are each independently selected from the group consisting of hydrogen, alkyl, and hydroxyalkyl.
 22. The method of claim 21 wherein the compound is of Formula Ia or a salt thereof,

wherein R¹ is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy; R³, R⁴, R⁵, and R⁶ are each independently selected from the group consisting of hydrogen, halogen, OH, alkyl, alkoxy, haloalkyl, haloalkoxy, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), NR⁹C(O)R¹⁰, and C(O)R¹¹, wherein R⁹ is selected from the group consisting of hydrogen and alkyl and R¹⁰ and R¹¹ are alkyl; X is selected from the group consisting of CH₂, O, S, NH, and N(CH₃); and Y is selected from the group consisting of OH, NH₂, N(H)OH, N(CH₃)OH, and N(R⁷R⁸); wherein when any one of R³, R⁴, R⁵, and R⁶ is N(R⁷R⁸), R⁷ and R⁸ are each independently selected from the group consisting of hydrogen and alkyl; and when Y is N(R⁷R⁸), R⁷ and R⁸ are each independently selected from the group consisting of hydrogen, alkyl, and hydroxyalkyl.
 23. The method of claim 21 wherein the compound is of Formula Ib or a salt thereof,

wherein R¹ is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy; R³, R⁴, R⁵, and R⁶ are each independently selected from the group consisting of hydrogen, halogen, OH, alkyl, alkoxy, haloalkyl, haloalkoxy, C₁ to C₄ hydroxyalkyl, N(R⁷R⁸), NR⁹C(O)R¹⁰, and C(O)R¹¹, wherein R⁹ is selected from the group consisting of hydrogen and alkyl and R¹⁰ and R¹¹ are alkyl; Y is selected from the group consisting of OH, NH₂, N(H)OH, N(CH₃)OH, and N(R⁷R⁸); and E is selected from the group consisting of S, O, and N(CH₃); wherein when any one of R³, R⁴, R⁵, and R⁶ is N(R⁷R⁸), R⁷ and R⁸ are each independently selected from the group consisting of hydrogen and alkyl; and when Y is N(R⁷R⁸), R⁷ and R⁸ are each independently selected from the group consisting of hydrogen, alkyl, and hydroxyalkyl.
 24. The method of claim 21 wherein R² is phenyl.
 25. The method of claim 21 wherein Z is phenyl.
 26. The method of claim 21 wherein Z is thienyl.
 27. The method of claim 21 wherein R¹ is selected from the group consisting of hydrogen, halogen, CH₃, OCH₃, CF₃, and OCF₃.
 28. The method of claim 21 wherein R¹ is hydrogen.
 29. The method of claim 21 wherein R¹ is halogen.
 30. The method of claim 21 wherein R³, R⁴, R⁵, and R⁶ are each independently selected from the group consisting of hydrogen, halogen, OH, CH₃, OCH₃, CF₃, and OCF₃.
 31. The method of claim 21 wherein R³, R⁴, R⁵, and R⁶ are each hydrogen.
 32. The method of claim 21 wherein X is a bond.
 33. The method of claim 21 wherein X is O.
 34. The method of claim 21 wherein Y is NH₂.
 35. The method of claim 21 where Y is OH. 